Anti-neurodegeneratively active 10-aminoaliphatyl-dibenzi b,f! oxepines

ABSTRACT

Base-substituted debenz b,f!oxepines of formula I ##STR1## wherein alk is a divalent aliphatic radical, R is an amino group that is unsubstituted or mono- or di-substituted by monovalent aliphatic and/or araliphatic radicals or disubstituted by divalent aliphatic radicals, and R 1 , R 2 , R 3  and R 4  are each, independently of the others, hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, and pharmaceutically acceptable salts thereof, may be used as anti-neurodegenerative active ingredients of medicaments. The invention relates also to novel compounds of formula I.

This is a Divisional of Ser. No. 08/594,215, filed Jan. 31, 1996 nowabandoned.

The invention relates to the use of 10-aminoaliphatyl-dibenzb,f!oxepines of formula I ##STR2## wherein alk is a divalent aliphaticradical, R is an amino group that is unsubstituted or mono- ordi-substituted by monovalent aliphatic and/or araliphatic radicals ordisubstituted by divalent aliphatic radicals, and

R₁, R₂, R₃ and R₄ are each, independently of the others, hydrogen, loweralkyl, lower alkoxy, halogen or trifluoromethyl,

and pharmaceutically acceptable salts thereof, as anti-neurodegenerativeactive ingredients of medicaments and in the preparation thereof, andalso to novel compounds of the formula I and salts thereof as such, toprocesses for the preparation thereof and to pharmaceutical compositionscomprising them.

Novel compounds of formula I are, for example, 10-aminoaliphatyl-dibenzb,f!oxepines in which

a1) when in each case alk is methylene: R is other than methylamino,dimethylamino, N'-methylpiperazino and N'-(2-hydroxyethyl)piperazino orat least one of the radicals R₁, R₂ and R₄ is other than hydrogen or R₃is other than hydrogen and 8-methoxy; R is other than dimethylamino anddiethylamino or at least one of the radicals R₁, R₂ and R₄ is other thanhydrogen or R₃ is other than 8-chloro; or: R is other than pyrrolidinoor at least one of the radicals R₁, R₂, R₃ and R₄ is other thanhydrogen,

b1) when alk is ethylene: R is other than methylamino or at least one ofthe radicals R₁, R₂ and R₄ is other than hydrogen or R₃ is other than6-methyl; or: R is other than diethylamino or at least one of theradicals R₁, R₂ and R₄ is other than hydrogen or R₃ is other than7-methyl or at least one of the radicals R₂, R₃ and R₄ is other thanhydrogen or R₁ is other than 3-methyl,

c1) when alk is ethylidene: R is other than methylamino anddimethylamino or at least one of the radicals R₁, R₂ and R₄ is differentfrom hydrogen, and d1) when alk is propylene: R is other thandimethylamino or at least one of the radicals R₁, R₂ and R₄ is otherthan hydrogen or R₃ is other than hydrogen or 8-triflluoromethyl; or atleast one of the radicals R₂, R₃ and R₄ is other than hydrogen or R₁ isother than hydrogen or 3-triflluoromethyl or at least one of theradicals R₂ and R₄ is different from form hydrogen or R₁ is other than3-chloro and R₃ is other than 8-chloro, or: R is other than piperidino,R₂, R₃ and R₄ are other than hydrogen or R₁ is other than 1-bromo or R₁,R₂ and R₄ are other than hydrogen or R₃ is other than 9-bromo;

preferably those in which

a2) alk is different from methylene or ethylidene when R is amino, loweralkylamino or di-lower alkylamino or is an alkyleneamino,oxaalkyleneamino, azaalkyleneamino, N'-lower alkylazaalkyleneamino,N'-hydroxyalkylazaalkyleneamino or N'-alkanoyloxyalkylazaalkyleneaminoradical having from 5 to 7 ring members that is bonded via nitrogen, R₁,R₂, R₃ and R₄ are hydrogen, lower alkyl, lower alkoxy, bromine orchlorine, and

b2) alk is diffrent fom ethylene, 1,2- und 1,3-propylene, 1,2-, 1,3- und1,4-butylene and 1,3-(2-methyl)propylene when R is a di-loweralkylamino, pyrrolidino, piperidino, N-lower alkylpiperidinyl,piperazino, N'-methylpiperazino, N'-formylpiperazino,N'-(2-hydroxyethyl)piperazino, N'-(2-acetoxyethyl)piperazino or N'-2-(2-hydroxyethoxy)ethyl!piperazino radical, R₁ and R₃ are hydrogen,lower alkyl, lower alkoxy, halogen or trifluoromethyl and and R₂ and R₄denote hydrogen, and

c2) alk is different from methylene and ethylene when R is loweralkylamino, R₁ and R₃ are hydrogen, hydroxy, lower alkyl or lower alkoxyand R₂ and R₄ are hydrogen.

Monovalent aliphatic radicals are, for example, lower alkyl, loweralkenyl or lower alkynyl groups that are unsubstituted or substituted byfree or etherified or esterified hydroxy or by unsubstituted oraliphatically substituted amino, such as lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, lower alkanoyloxy-lower alkyl, loweralkylamino-lower alkyl, di-lower alkylamino-lower alkyl, loweralkyleneamino-lower alkyl, lower alkenyl, hydroxy-lower alkenyl, loweralkoxy-lower alkenyl, lower alkanoyloxy-lower alkenyl, di-loweralkylamino-lower alkenyl, lower alkynyl, hydroxy-lower alkynyl, loweralkoxy-lower alkynyl, lower alkanoyloxy-lower alkynyl or di-loweralkylamino-lower alkynyl. Araliphatic radicals are, for example,phenyl-lower alkyl radicals that are unsubstituted or substituted bylower alkyl, lower alkoxy, halogen and/or by trifluoromethyl. Aminogroups that are mono- or di-substituted by monovalent aliphatic oraraliphatic radicals are therefore, for example, lower alkylamino;phenyl-lower alkylamino or phenyl-lower alkyl-lower alkylamino each ofwhich is unsubstituted or substituted by lower alkyl, lower alkoxy,halogen and/or by trifluoromethyl; hydroxy-lower alkylamino, loweralkoxy-lower alkylamino, lower alkanoyloxy-lower alkylamino, loweralkylamino-lower alkylamino, di-lower alkylamino-lower alkylamino, loweralkyleneamino-lower alkylamino, lower alkenylamino, hydroxy-loweralkenylamino, lower alkoxy-lower alkenylamino, lower alkanoyloxy-loweralkenylamino, di-lower alkylamino-lower alkenylamino, loweralkynylamino, hydroxy-lower alkynylamino, lower alkoxy-loweralkynylamino, lower alkanoyloxy-lower alkynylamino, di-loweralkylamino-lower alkynylamino, di-lower alkylamino, di(hydroxy-loweralkyl)amino, hydroxy-lower alkyl-lower alkylamino, di(lower alkoxy-loweralkyl)amino, lower alkoxy-lower alkyl-lower alkylamino, loweralkanoyloxy-lower alkylamino, lower alkanoyloxy-lower alkyl-loweralkylamino, di-lower alkylamino-lower alkylamino, di-loweralkylamino-lower alkyl-lower alkylamino, di-lower alkenylamino, loweralkenyl-lower alkylamino, hydroxy-lower alkenyl-lower alkylamino,di(lower alkoxy-lower alkenyl)amino, lower alkoxy-lower alkenyl-loweralkylamino, lower alkanoyloxy-lower alkenyl-lower alkylamino, di-loweralkylamino-lower alkenyl-lower alkylamino, lower alkynyl-loweralkylamino, lower alkoxy-lower alkynyl-lower alkylamino, loweralkanoyloxy-lower alkynyl-lower alkylamino or di-lower alkylamino-loweralkynyl-lower alkylamino.

Divalent aliphatic radicals are, for example, lower alkylene radicalsand, as a component of an amino group disubstituted by a divalentaliphatic radical, also aza-, oxa- or thia-lower alkylene radicals, suchas 3- or 4-aza-lower alkylene that is unsubstituted or N-substituted bylower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl or by loweralkanoyl, 3- or 4-oxa-lower alkylene or optionally S-oxidised 3- or4-thia-lower alkylene.

Amino groups disubstituted by divalent aliphatic radicals are, forexample, 3- to 8-membered lower alkyleneamino, 3- or 4-aza-loweralkyleneamino that is unsubstituted or N-substituted by lower alkyl,hydroxy-lower alkyl, lower alkoxy-lower alkyl or by lower alkanoyl, 3-or 4-oxa-lower alkyleneamino or optionally S-oxidised 3- or 4-thia-loweralkyleneamino, such as, especially, pyrrolidino, piperidino, di-loweralkylpiperidino, hexamethyleneimino, heptamethyleneimino, piperazino,N'-lower alkylpiperazino, N'-hydroxy-lower alkylpiperazino, N'-loweralkoxy-lower alkylpiperazino, N'-lower alkanoylpiperazino, morpholino,thiomorpholino, S-oxothiomorpholino or S,S-dioxothiomorpholino.

Hereinbefore and hereinafter there are to be understood by lowerradicals and compounds, for example, those having up to and including 7,preferably up to and including 4, carbon atoms.

Di(hydroxy-lower alkyl)amino is, for example, N,N-di(hydroxy-C₂ -C₄alkyl)amino, such as N,N-di(2-hydroxyethyl)amino orN,N-di(3-hydroxypropyl)amino.

Di(lower alkoxy-lower alkenyl)amino is, for example, N,N-di(C₁ -C₄alkoxy-C₂ -C₄ alkenyl)amino, such as N,N-di(4-methoxy-but-2-enyl)amino.

Di(lower alkoxy-lower alkyl)amino is, for example, N,N-di(C₁ -C₄alkoxy-C₁ -C₄ alkyl)amino, such as N,N-di(2-methoxyethyl)amino,N,N-di(2-ethoxyethyl)amino or N,N-di(3-methoxypropyl)amino.

Di-lower alkenylamino is, for example, N,N-di-C₂ -C₄ alkenylamino, suchas N,N-diallylamino or N-methallyl-N-allylamino.

Di-lower alkylamino is, for example, N,N-di-C₁ -C₄ alkylamino, such asdimethylamino, diethylamino, ethylmethylamino, dipropylamino,methylpropylamino, ethylpropylamino, dibutylamino or butylmethylamino.

Di-lower alkylamino-lower alkenyl-lower alkylamino is, for example,N-(di-C₁ -C₄ alkylamino-C₂ -C₄ alkenyl)-N-C₁ -C₄ alkylamino, such asN-(4-dimethylaminobut-2-enyl)-N-methylamino.

Di-lower alkylamino-lower alkenylamino is, for example, N-(di-C₁ -C₄alkylamino-C₂ -C₄ -alkenyl)amino, such asN-(4-dimethylaminobut-2-enyl)amino.

Di-lower alkylamino-lower alkynylamino is, for example, N-(di-C₁ -C₄alkylamino-C₂ -C₄ -alkynyl)amino, such asN-(4-dimethylaminobut-2-ynyl)amino.

Di-lower alkylamino-lower alkyl-lower alkylamino is, for example,N-(di-C₁ -C₄ alkylamino-C₂ -C₄ alkyl)-N-C₁ -C₄ alkylamino, such asN-(2-dimethylaminoethyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-ethylamino,N-(3-dimethylaminopropyl)-N-methylamino orN-(4-dimethylaminobutyl)-N-methylamino.

Di-lower alkylamino-lower alkylamino is, for example, N-(di-C₁ -C₄alkylamino-C₂ -C₄ alkyl)amino, such as N-(2-dimethylaminoethyl)amino,N-(2-dimethylaminoethyl)amino, N-(3-dimethylaminopropyl)amino orN-(4-dimethylaminobutyl)amino.

Halogen is, for example, halogen having an atomic number of up to andincluding 35, such as chlorine or bromine.

Hydroxy-lower alkenyl-lower alkylamino is, for example, N-(hydroxy-C₂-C₄ alkenyl)-N-(C₁ -C₄ alkylamino, such asN-(4-hydroxybut-2-enyl)-N-methylamino.

Hydroxy-lower alkenylamino is, for example, hydroxy-C₂ -C₄ alkenylamino,such as 4-hydroxybut-2-enylamino.

Hydroxy-lower alkynylamino is, for example, hydroxy-C₂ -C₄ alkynylamino,such as 4-hydroxybut-2-ynylamino.

Hydroxy-lower alkyl-lower alkylamino is, for example, N-(hydroxy-C₂ -C₄alkyl)-N-C₁ -C₄ alkyl-amino, such as N-(2-hydroxyethyl)-N-methylamino,N-(3-hydroxypropyl)-N-methylamino or N-(4-hydroxybutyl)-N-methylamino.

Hydroxy-lower alkylamino is, for example, hydroxy-C₂ -C₄ alkylamino,such as 2-hydroxyethylamino, 3-hydroxypropylamino or4-hydroxybutylamino.

N'-Hydroxy-lower alkylpiperazino is, for example, N'-(hydroxy-C₁ -C₄alkyl)piperazino, such as N'-(2-hydroxyethyl)piperazino orN'-(3-hydroxypropyl)piperazino.

N'-Lower alkanoylpiperazino is, for example, N'-C₁ -C₇alkanoylpiperazino, such as N'-acetylpiperazino.

N'-Lower alkoxy-lower alkylpiperazino is, for example, N'-(C₁ -C₄alkoxy-C₁ -C₄ alkyl)piperazino, such as N'-(2-methoxyethyl)piperazino orN'-(3-methoxypropyl)piperazino.

N'-Lower alkylpiperazino is, for example, N'-C₁ -C₄ alkylpiperazino,such as N'-methylpiperazino, N'-ethylpiperazino, N'-propylpiperazino orN'-butylpiperazino.

Lower alkoxy is, for example, C₁ -C₇ alkoxy, preferably C₁ -C₇ alkoxy,such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy,sec-butyloxy, tert-butyloxy, pentyloxy or a hexyloxy or heptyloxy group.

Lower alkanoyloxy-lower alkenyl-lower alkylamino is, for example, N-(C₁-C₇ alkanoyloxy-C₂ -C₄ alkenyl)-N-(C₁ -C₄ alkyl)amino, such asN-(4-acetoxybut-2-enyl)-N-methylamino.

Lower alkanoyloxy-lower alkenylamino is, for example, N-(C₁ -C₇alkanoyloxy-C₂ -C₄ -alkenyl)amino, such as N-(4-acetoxybut-2-enyl)amino.

Lower alkanoyloxy-lower alkynyl-lower alkylamino is, for example, N-(C₁-C₇ alkanoyloxy-C₂ -C₄ alkynyl)-N-(C₁ -C₄ alkyl)amino, such asN-(4-acetoxybut-2-ynyl)-N-methylamino.

Lower alkanoyloxy-lower alkynylamino is, for example, N-(C₁ -C₇alkanoyloxy-C₂ -C₄ -alkynyl)amino, such as N-(4-acetoxybut-2-ynyl)amino.

Lower alkanoyloxy-lower alkyl-lower alkylamino is, for example, N-(C₁-C₇ alkanoyloxy-C₂ -C₄ -alkyl)-N-(C₁ -C₄ alkyl)amino, such asN-(2-acetoxyethyl)-N-methylamino, N-(2-acetoxyethyl)-N-ethylamino,N-(3-acetoxypropyl)-N-methylamino or N-(4-acetoxybutyl)-N-methylamino.

Lower alkanoyloxy-lower alkylamino is, for example, N-(C₁ -C₇alkanoyloxy-C₂ -C₄ alkyl)amino, such as N-(2-acetoxyethyl)amino,N-(3-acetoxypropyl)amino or N-(4-acetoxybutyl)amino.

Lower alkenyl-lower alkylamino is, for example, N-(C₂ -C₇ alkenyl)-N-(C₂-C₇ alkyl)amino, especially N-(C₂ -C₄ alkenyl)-N-(C₁ -C₄ alkyl)amino,such as N-vinyl-N-methylamino, N-allyl-N-methylamino,N-allyl-N-ethylamino, N-but-2-enyl-N-methylamino orN-but-3-enyl-N-methyl amino. Lower alkenylamino is, for example, N-(C₂-C₇ alkenyl)amino, especially N-(C₂ -C₄ -alkenyl)amino, amino, such asvinylamino, allylamino, but-2-enylamino or N-but-3-enylamino, especiallyallylamino.

Lower alkynyl-lower alkylamino is, for example, N-(C₂ -C₄ alkynyl)-N-(C₁-C₄ alkyl)amino, such as N-propargyl-N-methylamino,N-but-2-ynyl-N-methylamino or N-but-3-ynyl-N-methylamino.

Lower alkynylamino is, for example, N-(C₂ -C₇ alkynyl)amino, especiallyN-(C₂ -C₄ alkynyl)amino, such as propargylamino, but-2-ynylamino orN-but-3-ynylamino, especially propargylamino.

Lower alkoxy is, for example, C₁ -C₇ alkoxy, preferably C₁ -C₄ alkoxy,such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, but mayalso be isobutyloxy, sec-butyloxy, tert-butyloxy or a C₅ -C₇ alkoxygroup, such as a pentyloxy, hexyloxy or heptyloxy group.

Lower alkoxy-lower alkenyl-lower alkylamino is, for example, N-(C₁ -C₄alkoxy-C₂ -C₄ alkenyl)-N-(C₁ -C₄ alkyl)amino, such asN-(4-methoxybut-2-enyl)-N-methylamino,N-(4-methoxybut-2-enyl)-N-ethylamino orN-(4-ethoxybut-2-enyl)-N-methylamino.

Lower alkoxy-lower alkenylamino is, for example, N-(C₁ -C₄ alkoxy-C₂ -C₄alkenyl)amino, such as N-(4-methoxybut-2-enyl)amino orN-(4-ethoxybut-2-enyl)amino.

Lower alkoxy-lower alkynyl-lower alkylamino is, for example, N-(C₁ -C₄alkoxy-C₂ -C₄ alkynyl)-N-(C₁ -C₄ alkyl)amino, such asN-(4-methoxybut-2-ynyl)-N-methylamino,N-(4-methoxybut-2-ynyl)-N-ethylamino orN-(4-ethoxybut-2-ynyl)-N-methylamino.

Lower alkoxy-lower alkynylamino is, for example, N-(C₁ -C₄ alkoxy-C₂ -C₄alkynyl)amino, such as N-(4-methoxybut-2-ynyl)amino,N-(4-ethoxybut-2-ynyl)amino or N-(4-propyloxybut-2-ynyl)amino.

Lower alkoxy-lower alkylamino is, for example, C₁ -C₄ alkoxy-C₂ -C₄alkylamino, such as 2-methoxyethylamino, 2-ethoxyethylamino,2-propyloxyethylamino, 3-methoxypropylamino, 3-ethoxypropylamino,4-methoxybutylamino, 2-isopropyloxyethylamino or 2-butyloxyethylamino.

Lower alkoxy-lower alkyl-lower alkylamino is, for example, N-(C₁ -C₄alkoxy-C₂ -C₄ alkyl)-N-(C₁ -C₄ alkyl)amino, such asN-(2-methoxyethyl)-N-methylamino, N-(2-ethoxyethyl)-N-methylamino,N-(2-propyloxyethyl)-N-methylamino, N-(3-methoxypropyl)-N-methylamino,3-ethoxypropylamino or N-(4-methoxybutyl)-N-methylamino.

Lower alkyl is, for example, C₁ -C₇ alkyl, preferably C₁ -C₄ alkyl, suchas methyl, ethyl, propyl, isopropyl or butyl, but may also be isobutyl,sec-butyl, tert-butyl or a C₅ -C₇ alkyl group, such as a pentyl, hexylor heptyl group.

Lower alkylamino is, for example, C₁ -C₇ alkylamino, preferably C₁ -C₄alkylamino, such as methylamino, ethylamino, propylamino, isopropylaminoor butylamino, but may also be isobutylamino, sec-butylamino ortert-butylamino or a C₅ -C₇ alkylamino group, such as a pentylamino,hexylamino or heptylamino group, and is especially methylamino orpropylamino.

Lower alkylamino-lower alkylamino is, for example, N-(C₁ -C₄alkylamino-C₂ -C₄ alkyl)amino, such as N-(2-methylaminoethyl)amino,N-(3-methylaminopropyl)amino, N-(4-methylaminobutyl)amino,N-(2-ethylaminoethyl)amino, N-(3-ethylaminopropyl)amino orN-(4-ethylaminobutyl)amino.

Lower alkyleneamino-lower alkylamino is, for example, 3- to 8-memberedalkyleneamino-C₂ -C₄ alkylamino, such as 2-pyrrolidinoethylamino,2-piperidinoethylamino, 2-dimethylpiperidinoethylamino,2-hexamethyleneiminoethylamino, 3-pyrrolidinopropylamino,3-piperidinopropylamino, 3-dimethylpiperidinopropylamino or3-hexamethyleneiminopropylamino.

Phenyl-lower alkyl-lower alkylamino is, for example, N-(phenyl-C₁ -C₄alkyl)-N-(C₁ -C₄ alkyl)amino, such as N-benzyl-N-methylamino,N-(2-phenylethyl)-N-methylamino or N-(4-phenylbutyl)-N-methylamino.

Phenyl-lower alkylamino is, for example, phenyl-C₁ -C₄ alkylamino, suchas benzylamino, 1- or 2-phenylethylamino, 3-phenylpropylamino or4-phenylbutylamino.

Salts of compounds of formula I are, for example, the pharmaceuticallyacceptable acid addition salts thereof with suitable mineral acids, suchas hydrohalic acids, sulfuric acid or phosphoric acid, for examplehydrochlorides, hydrobromides, sulfates, hydrogen sulfates orphosphates, or salts with suitable aliphatic or aromatic sulfonic acidsor N-substituted sulfamic acids, for example methanesulfonates,benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfamates(cyclamates).

Some of the compounds of formula I proposed for use in accordance withthe invention are already known. For example there are proposed inGerman Offenlegungsschrift No. 1 793 521 as adrenolytic and centralnervous system-dampening active ingredients of medicaments, such assedative and narcosis-potentiating active ingredients of medicaments,compounds of formula I wherein alk is methylene or ethylidene and R isamino, methylamino, ethylamino, propylamino, isopropylamino, butylamino,isobutylamino, dimethylamino, diethylamino, dipropylamino, pyrrolidino,piperidino, morpholino, N'-methylpiperazino,N'-(2-hydroxyethyl)piperazino, N'-(2-acetoxyethyl)piperazino,N'-(2-pivaloyloxyethyl)piperazino or N'-methylhomopiperazino and R₁, R₂,R₃ and R₄ are hydrogen, lower alkyl, lower alkoxy and/or halogen.

The invention is based on the surprising discovery that compounds offormula I, at doses of approximately 0.1 mg/kg s.c. and belowadministered to newborn rats in an experimental procedure according toAusari et al, J. Neuroscience 13, 4042-4053 (1993), exhibit a pronouncedprotective action on facial motor neurons against apoptotic necrocytosisand, after the administration of 0.275 mg/kg s.c. and below to fullygrown rats in an experimental procedure according to Golowitz andPaterson, Soc. Neurosc. Abstr. 20, 246, 113.2 (1994), exhibit apronounced protective action on hippocampus pyramidal cells for a periodof 4 days against necrocytosis caused by the administration of kainicacid.

The compounds of formula I and pharmaceutically acceptable salts thereofare accordingly, in additon to their previously known adrenolytic andcentral nervous system-dampening use, preferentially suited to theprophylactic or therapeutic treatment of neurodegenerative disorders,especially those in which apoptotic necrocytosis plays a part, such ascerebral ischaemias, Alzheimer's and Parkinson's disease, amyotrophiclateral sclerosis, glaucoma and also general or diabetic peripheralneuropathies.

The invention relates in the first line to the use of compounds offormula I wherein alk is lower alkylene,

R is amino, lower alkylamino; phenyl-lower alkylamino or phenyl-loweralkyl-lower alkylamino each of which is unsubstituted or substituted bylower alkyl, lower alkoxy, halogen and/or by trifluoromethyl;hydroxy-lower alkylamino, lower alkoxy-lower alkylamino, loweralkanoyloxy-lower alkylamino, lower alkylamino-lower alkylamino,di-lower alkylamino-lower alkylamino, lower alkyleneamino-loweralkylamino, lower alkenylamino, hydroxy-lower alkenylamino, loweralkoxy-lower alkenylamino, lower alkanoyloxy-lower alkenylamino,di-lower alkylamino-lower alkenylamino, lower alkynylamino,hydroxy-lower alkynylamino, lower alkoxy-lower alkynylamino, loweralkanoyloxy-lower alkynylamino, di-lower alkylamino-lower alkynylamino,di-lower alkylamino, di(hydroxy-lower alkyl)amino, hydroxy-loweralkyl-lower alkylamino, di(lower alkoxy-lower alkyl)amino, loweralkoxy-lower alkyl-lower alkylamino, lower alkanoyloxy-lower alkylamino,lower alkanoyloxy-lower alkyl-lower alkylamino, di-loweralkylamino-lower alkylamino, di-lower alkylamino-lower alkyl-loweralkylamino, di-lower alkenylamino, lower alkenyl-lower alkylamino,hydroxy-lower alkenyl-lower alkylamino, di(lower alkoxy-loweralkenyl)amino, lower alkoxy-lower alkenyl-lower alkylamino, loweralkanoyloxy-lower alkenyl-lower alkylamino, di-lower alkylamino-loweralkenyl-lower alkylamino, lower alkynyl-lower alkylamino, loweralkoxy-lower alkynyl-lower alkylamino, lower alkanoyloxy-loweralkynyl-lower alkylamino, di-lower alkylamino-lower alkynyl-loweralkylamino, 3- to 8-membered lower alkyleneamino; 3- or 4-aza-loweralkyleneamino that is unsubstituted or N-substituted by lower alkyl,hydroxy-lower alkyl, lower alkoxy-lower alkyl or by lower alkanoyl; 3-or 4-oxa-lower alkyleneamino or optionally S-oxidised 3- or 4-thia-loweralkyleneamino and

R₁, R₂, R₃ and R₄ are each, independently of the others, hydrogen, loweralkyl, lower alkoxy, halogen or trifluoromethyl,

and pharmaceutically acceptable salts thereof, and also to novelcompounds as defined above of formula I as such, especially those inwhich R is other than amino that is unsubstituted or mono- ordi-substituted by lower alkyl, pyrrolidino, piperidino, morpholino,N'-methylpiperazino, N'-(2-hydroxyethyl)piperazino,N'-(2-acetoxyethyl)piperazino. N'-(2-pivaloyloxyethyl)piperazino andN'-methylhomopiperazino when alk is methylene or ethylidene and R₁, R₂,R₃ and R₄ are hydrogen, lower alkyl, lower alkoxy and/or halogen, and tosalts thereof.

The invention relates especially to the use of compounds of formula Iwherein alk is lower alkylene,

R is amino, lower alkylamino; phenyl-lower alkylamino or phenyl-loweralkyl-lower alkylamino each of which is unsubstituted or substituted bylower alkyl, lower alkoxy, halogen and/or by trifluoromethyl; loweralkenylamino, lower alkynylamino, di-lower alkylamino, 3- to 8-memberedlower alkyleneamino; 3- or 4-aza-lower alkyleneamino that isunsubstituted or N-substituted by lower alkyl, hydroxy-lower alkyl,lower alkoxy-lower alkyl or by lower alkanoyl; 3- or 4-oxa-loweralkyleneamino or optionally S-oxidised 3- or 4-thia-lower alkyleneaminoand

R₁, R₂, R₃ and R₄ are each, independently of the others, hydrogen, loweralkyl, lower alkoxy, halogen or trifluoromethyl,

and pharmaceutically acceptable salts thereof, and also novel compoundsas defined above of formula I as such, especially those in which R isother than amino that is unsubstituted or mono- or di-substituted bylower alkyl, pyrrolidino, piperidino, morpholino, N'-methylpiperazino,N'-(2-hydroxyethyl)piperazino, N'-(2-acetoxyethyl)piperazino,N'-(2-pivaloyloxyethyl)piperazino and N'-methylhomopiperazino when alkis methylene or ethylidene and R₁, R₂, R₃ and R₄ are hydrogen, loweralkyl, lower alkoxy and/or halogen, and to salts thereof as well as toprocesses for the preparation thereof.

The invention relates especially to the use of compounds of formula Iwherein alk is methylene,

R is amino, C₁ -C₄ alkylamino, such as methylamino, ethylamino,propylamino or butylamino; phenyl-C₁ -C₄ alkylamino, such as benzylaminoor phenethylamino, that is unsubstituted or substituted by C₁ -C₄ alkyl,such as methyl, C₁ -C₄ alkoxy, such as methoxy, halogen having an atomicnumber of up to and including 35, such as chlorine or bromine, and/or bytrifluoromethyl; phenyl-C₁ -C₄ alkyl-C₁ -C₄ alkylamino, such asN-benzyl-N-methylamino, that is unsubstituted or substituted by C₁ -C₄alkyl, such as methyl, C₁ -C₄ alkoxy, such as methoxy, halogen having anatomic number of up to and including 35, such as chlorine or bromine,and/or by trifluoromethyl; C₂ -C₇ alkenylamino, such as allylamino,methallylamino or but-2-enylamino, C₂ -C₇ alkynylamino, such aspropargylamino or but-2-ynylamino, N-C₂ -C₇ alkenyl-N-C₁ -C₄ alkylamino,such as N-allyl-N-methylamino, N-allyl-N-ethylamino,N-methallyl-N-methylamino or N-but-2-enyl-N-methylamino, N-C₂ -C₇alkynyl-N-C₁ -C₄ alkylamino, such as N-propargyl-N-methylamino,N-propargyl-N-ethylamino or N-but-2-ynyl-N-methylamino, di-C₁ -C₄alkylamino, such as dimethylamino, diethylamino, N-methyl-N-propylaminoor N-butyl-N-methylamino, pyrrolidino, piperidino, morpholino,piperazino, N'-C₁ -C₄ alkylpiperazino, such as N'-methylpiperazino, orN'-(hydroxy-C₂ -C₄ alkyl)piperazino, such asN'-(2-hydroxyethyl)piperazino, and

R₁, R₂, R₃ and R₄ are each, independently of the others, hydrogen, C₁-C₄ alkyl, such as methyl, C₁ -C₄ alkoxy, such as methoxy, halogenhaving an atomic number of up to and including 35, such as chlorine orbromine, or trifluoromethyl,

and pharmaceutically acceptable salts thereof, and also to novelcompounds as defined above of formula I as such, especially those inwhich R is other than amino, C₁ -C₄ alkylamino, di-C₁ -C₄ alkylamino,pyrrolidino, piperidino, morpholino and N'-methylpiperazino when R₁, R₂,R₃ and R₄ are hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy and/or halogen, andto salts thereof as well as to processes for the preparation thereof.

The invention relates more especially to compounds of formula I whereinalk is methylene,

R is C₂ -C₇ alkenylamino, such as allylamino, methallylamino orbut-2-enylamino, C₂ -C₇ alkynylamino, such as propargylamino orbut-2-ynylamino, N-C₂ -C₇ alkenyl-N-C₁ -C₄ alkylamino, such asN-allyl-N-methylamino, N-allyl-N-ethylamino, N-methallyl-N-methylaminoor N-but-2-enyl-N-methylamino, N-C₂ -C₇ alkynyl-N-C₁ -C₄ alkylamino,such as N-propargyl-N-methylamino, N-propargyl-N-ethylamino orN-but-2-ynyl-N-methylamino, or pPyrrolidino, piperidino or morpholino,

R₁ and R₃ are each, independently of the others, hydrogen, C₁ -C₄ alkyl,such as methyl, C₁ -C₄ alkoxy, such as methoxy, halogen having an atomicnumber of up to and including 35, such as chlorine or bromine, ortrifluoromethyl, and

R₂ and R₄ are hydrogen,

and to salts thereof, and to processes for the preparation thereof aswell as to the use thereof.

The invention relates most especially to compounds of formula I whereinalk is methylene,

R is C₂ -C₇ alkenylamino, such as allylamino, methallylamino orbut-2-enylamino, C₂ -C₇ alkynylamino, such as propargylamino orbut-2-ynylamino, N-C₂ -C₇ alkenyl-N-C₁ -C₄ alkylamino, such asN-allyl-N-methylamino, N-allyl-N-ethylamino, N-methallyl-N-methylaminoor N-but-2-enyl-N-methylamino, N-C₂ -C₇ alkynyl-N-C₁ -C₄ alkylamino,such as N-propargyl-N-methylamino, N-propargyl-N-ethylamino orN-but-2-ynyl-N-methylamino, or phenyl-C₁ -C₄ alkylamino, such asbenzylamino or phenethylamino, that is unsubstituted or substituted byC₁ -C₄ alkyl, such as methyl, C₁ -C₄ alkoxy, such as methoxy, halogenhaving an atomic number of up to and including 35, such as chlorine orbromine, and/or by trifluoromethyl, and

R₁, R₂, R₃ and R₄ are hydrogen,

and to salts thereof, and to processes for the preparation thereof aswell as to the use thereof.

The invention relates specifically to the use of

N-(dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine;

N-allyl-N-(dibenz b,f!oxepin-10-ylmethyl)amine;

N-allyl-N-(dibenz b,f!oxepin-10-ylmethyl)-N-methylamine;

N-(dibenz b,f!oxepin-10-ylmethyl)amine;

N-(dibenz b,f!oxepin-10-ylmethyl)-N-prop-2-ynylamine;

N-(dibenz b,f!oxepin-10-ylmethyl)-N-propylamine;

N-(dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-propylamine;

1-dibenz b,f!oxepin-10-ylmethyl-piperidine;

4-dibenz b,f!oxepin-10-ylmethyl-morpholine;

N-(1-chloro-dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine;

1-(1-chloro-dibenz b,f!oxepin-10-ylmethyl)-pyrrolidine;

N-(1-chloro-dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-propylamine;

N-methyl-N-prop-2-ynyl-N-(3-trifluoromethyl-dibenzb,f!oxepin-10-ylmethyl)amine

1-(3-trifluoromethyl-dibenz b,f!oxepin-10-ylmethyl)-pyrrolidine;

N-(7-chloro-dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine;

1-(7-chloro-dibenz b,f!oxepin- 10-ylmethyl)-pyrrolidine;

N-(8-methoxy-dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine;

N-(8-tert-butyl-dibenzb,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine;

1-(8-tert-butyl-dibenz b,f!oxepin-10-ylmethyl)-pyrrolidine;

N-(6-chloro-dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine;

1-(6-chloro-dibenz b,f!oxepin-10-ylmethyl)pyrrolidine;

N-(1-fluoro-dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine;

1-(1-fluoro-dibenz b,f!oxepin-10-ylmethyl)pyrrolidine;

N-(dibenz b,f!oxepin-10-ylmethyl)-N-benzylamine;

N-benzyl-N-(dibenz b,f!oxepin-10-ylmethyl)-N-methylamine;

N-(dibenz b,f!oxepin-10-ylmethyl)-N-propyl-N-benzylamine;

N-allyl-N-benzyl-N-(dibenz b,f!oxepin-10-ylmethyl)amine;

1-(dibenz b,f!oxepin-10-ylmethyl)-4-methyl-piperazine;

1-(dibenz b,f!oxepin-10-ylmethyl)-4-(2-hydroxyethyl)-piperazine;

N, N-diethyl-N-(dibenz b,f!oxepin-10-ylmethyl)amine;

N-(dibenz b,f!oxepin-10-ylmethyl)-N,N-dimethylamine;

N-(dibenz b,f!oxepin-10-ylmethyl)-N-methylamine;

1-(dibenz b,f!oxepin-10-ylmethyl)pyrrolidine;

N- 1-(dibenz(b,f!oxepin-10-ylethyl)-N,N-dimethylamine;

N-(1-(dibenz b,f!oxepin- 10-ylethyl)-N-methylamine;

1-(8-methoxy-dibenz b,f!oxepin-10-ylmethyl)-4-methyl-piperazine;

N-(8-methoxy-dibenz b,f!oxepin- 10-ylmethyl)-N,N-dimethylamine;

N-(8-methoxy-dibenz b,f!oxepin-10-ylmethyl)-N-methylamine:

N-(dibenz b,f!oxepin-10-ylmethyl)amine;

N-butyl-N-(dibenz b,f!oxepin-10-ylmethyl)amine;

N-(8-chloro-dibenz b,f!oxepin- 10-ylmethyl)-N,N-dimethylamine and

N-(8-chloro-dibenz b,f!oxepin- 10-ylmethyl)-N,N-diethylamine

and of pharmaceutically acceptable salts thereof, and also to

N-(dibenz b,f!oxepin- 10-ylmethyl)-N-methyl-N-prop-2-ynylamine;

N-allyl-N-(dibenz b,f!oxepin-10-ylmethyl)amine;

N-allyl-N-(dibenz b,f!oxepin-10-ylmethyl)-N-methylamine;

N-(dibenz b,f!oxepin-10-ylmethyl)amine;

N-(dibenz b,f!oxepin-10-ylmethyl)-N-prop-2-ynylamine;

N-(dibenz b,f!oxepin-10-ylmethyl)-N-propylamine;

N-(dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-propylamine;

1-dibenz b,f!oxepin-10-ylmethyl-piperidine;

4-dibenz b,f!oxepin-10-ylmethyl-morpholine;

N-(1-chloro-dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine;

1-(1-chloro-dibenz b,f!oxepin-10-ylmethyl)-pyrrolidine;

N-(1-chloro-dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-propylamine;

N-methyl-N-prop-2-ynyl-N-(3-trifluoromethyl-dibenzb,f!oxepin-10-ylmethyl)amine;

1-(3-trifluoromethyl-dibenz b,f!oxepin-10-ylmethyl)-pyrrolidine;

N-(7-chloro-dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine;

1-(7-chloro-dibenz b,f!oxepin-10-ylmethyl)-pyrrolidine;

N-(8-methoxy-dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine;

N-(8-tert-butyl-dibenzb,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine;

1-(8-tert-butyl-dibenz b,f!oxepin-10-ylmethyl)-pyrrolidine;

N-(6-chloro-dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine;

1-(6-chloro-dibenz b,f!oxepin-10-ylmethyl)pyrrolidine;

N-(1-fluoro-dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine;

1-(1-fluoro-dibenz b,f!oxepin-10-ylmethyl)pyrrolidine;

N-benzyl-N-(dibenz b,f!oxepin-10-ylmethyl)amine;

N-benzyl-N-(dibenz b,f!oxepin-10-ylmethyl)-N-methylamine;

N-(dibenz b,f!oxepin-10-ylmethyl)-N-propyl-N-benzylamine and

N-allyl-N-benzyl-N-(dibenz b,f!oxepin-10-ylmethyl)amine

themselves, to processes for the preparation thereof and topharmaceutical compositions comprising them.

The process for the preparation of novel compounds of formula Icomprises

a) condensing a compound of formula II ##STR3## with a compound offormula III

    Y--R                                                       (III)

wherein one of the radicals X and Y is reactive esterified hydroxy andthe other is free or temporarily protected amino, and R, R₁, R₂, R₃ andR₄ are as defined hereinbefore, and removing again the amino-protectinggroup that may have been temporarily introduced, or

b) in a compound of formula IV ##STR4## wherein alk' is a lower alkylenegroup substituted by oxo or by free or esterified hydroxy, reducing thegroup alk' with replacement of the oxygen function to form thecorresponding group alk

and, if desired, in each case converting a compound obtainable inaccordance with the process into a different compound of formula I,separating a mixture of isomers obtainable in accordance with theprocess into its components and isolating the desired isomer, and/orconverting a salt obtainable in accordance with the process into thefree compound or converting a free compound obtainable in accordancewith the process into a salt.

Reactive esterified hydroxy in starting materials of formulae II and IIIin accordance with process variant a) is, for example, hydroxyesterified with a hydrohalic acid or an organic sulfonic acid, such ashalogen, for example chlorine, bromine or iodine, or unsubstituted orlower-alkyl-, halo- and/or nitro-substituted benzenesulfonyloxy, such asbenzenesulfonyloxy, p-bromobenzenesulfonyloxy or p-toluenesulfonyloxy,or lower alkanesulfonyloxy, such as methanesulfonyloxy.

The reaction of compounds of formulae II and III is carried out incustomary manner, for example in the presence of a basic condensingagent, such as a tertiary or sterically hindered binary organic nitrogenbase, such as a tri-lower alkylamine or sterically hindered di-loweralkylamine, such as triethylamine or diisopropylamine, or aheteroaromatic base, such as pyridine or dimethylaminopyridine,advantageously in an organic solvent, such as toluene, and, ifnecessary, with cooling or heating, for example in a temperature rangeof from approximately 0° to approximately 80° C.

Suitable amino-protecting groups for the intermediate protection ofprimary amino groups are customary amino-protecting groups, especiallyamino-protecting groups that can be removed by solvolysis. Such groupsare, for example, acyl groups derived from a carboxylic acid or from asemi-ester of carbonic acid, such as unsubstituted or halogenated loweralkanoyl, for example lower alkanoyl, such as formyl, acetyl orpivaloyl, polyhalo-lower alkanoyl, such as trifluoroacetyl, loweralkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl,isopropyloxycarbonyl or tert-butyloxycarbonyl, or unsubstituted orsubstituted phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, andalso silyl groups, such as tri-lower alkylsilyl, for exampletrimethylsilyl.

The removal of those amino-protecting groups is carried out in customarymanner, for example by treatment with a solvolysis agent, such as waterin the presence of an acid, for example an aqueous mineral acid, such asa hydrohalic acid, or an alkali metal hydroxide, such as sodiumhydroxide solution or potassium hydroxide solution or, especially forthe removal of tri-lower alkoxycarbonyl, a sulfonic acid, such asmethanesulfonic acid in a halogenated hydrocarbon, such asdichloromethane, or, especially for the removal of formyl, a suitablesilyl compound, such as a tri-lower alkylsilyl halide, such astrimethylsilyl bromide, or a disilazane, such as hexamethyldisilazane.

The starting materials of formulae II and III are known or can beprepared analogously to the method of preparation of known compounds offormulae II and III.

For example, compounds of formula II wherein alk is methylene and X isreactively esterified hydroxy are obtained, for example, as follows:compounds of formulae V and VI ##STR5## wherein X₁ is halogen and X₂ ishydrogen or hydroxy, are condensed with one another in customary manner,the condensation being carried out preferably in a temperature range offrom approximately 100° C. to approximately 180° C. and, when using asstarting materials compounds of formula V wherein X₂ is hydroxy and X₁is, for example, chlorine, preferably in the presence ofcopper/copper(I) iodide and, when using as starting materials compoundsof formula V wherein X₂ is hydrogen and X₁ is, for example, fluorine,preferably in the presence of potassium carbonate in dimethylacetamide,the group --C(═P)--X₁ in a resulting compound of formula VII ##STR6## isreduced to hydroxymethyl in customary manner, for example by treatmentwith a di-light metal hydride, such as lithium aluminium hydride intetrahydrofuran, the hydroxymethyl group is converted into halomethyl incustomary manner, for example by heating with a hydrohalic acid,especially hydrobromic acid, the halogen atom is replaced by cyano incustomary manner, for example by treatment with an alkali metal cyanide,such as sodium cyanide in ethanol, and the resulting compound of formulaVIII ##STR7## is reacted in customary manner, for example in thepresence of an alkali metal alkanolate, such as sodium methanolate withan oxalic acid di-lower alkyl ester, for example diethyl oxalate, workedup under acidic conditions, and the carboxy group in the resultingcompound of formula IX ##STR8## is reduced to hydroxymethyl in customarymanner, for example by treatment with a haloformic acid ester, such asisobutyl chloroformate, in the presence of a nitrogen base, such asN-methylmorpholine, preferably in an ethereal solvent, such asdimethoxymethane, and then with a di-light metal hydride, such as sodiumborohydride in water, and the resulting compound of formula X ##STR9##is treated with an agent that introduces the group X, such as ahydrohalic acid or a sulfonyl halide, such as methanesulfonyl chloride.

Higher homologues of compounds of formula II wherein alk is ethylene,propylene etc. or ethylidene, propylidene etc. may be obtained by, forexample, at the stage of the acid IX, either carrying out a chainlengthening in customary manner or converting the carboxy group into thedesired 1-oxoalkyl group in customary manner.

Compounds of formula II wherein X is free or protected amino can beobtained, for example, from the reactive esters obtained as describedabove, by customary saturated solution of ammonia in methanol and, ifdesired, subsequent introduction of the amino-protecting group incustomary manner.

In starting materials of formula IV according to process variant b),esterified hydroxy is, for example, hydroxy esterified with a carboxylicacid or with a semiester of carbonic acid, such as unsubstituted orhalogenated lower alkanoyloxy, for example lower alkanoyloxy, such asformyloxy, acetyloxy or pivaloyloxy, lower alkoxycarbonyloxy, such asmethoxycarbonyloxy, ethoxycarbonyloxy, isopropyloxycarbonyloxy ortert-butyloxycarbonyloxy, or unsubstituted or substituted phenyl-loweralkoxycarbonyloxy, such as benzyloxycarbonyloxy.

The reduction of compounds of formula IV is carried out in customarymanner, for example by treatment with a di-light metal hydride, such aslithium aluminium hydride in tetrahydrofuran.

Starting materials of formula IV wherein alk' is ω-oxo-lower alkylbonded to the group R in the ω-position can be obtained, for example,from the corresponding acids of formula IX or the homologues thereof byreaction with an amine of formula III, wherein Y is free or temporarilyprotected amino, in customary manner, for example by treatment with anacid halogenating agent, such as oxalyl chloride in the presence ofdimethylformamide. It is then possible from those starting materials, bymeans of partial reduction and, if desired, esterification, to obtainthe corresponding compounds of formula IV wherein alk' is lower alkylenesubstituted by free or esterified hydroxy. Starting materials of formulaIV wherein alk' is (ω-1)-oxo-lower alkyl bonded to the group R in theω-position can be obtained, for example, from the corresponding methylketones by halogenation, for example by means of N-bromo- orN-chloro-succinimide, and subsequent reaction with an amine of formulaII wherein Y is free or temporarily protected amino.

Compounds obtainable in accordance with the process may be converted incustomary manner into different compounds of formula I.

For example, in compounds of formula I wherein R is unsubstituted amino,the amino group may be substituted in customary manner by one or twoidentical or different monovalent aliphatic or araliphatic radicals orby a divalent aliphatic radical. In an analogous manner, it is alsopossible in compounds of formula I wherein R is amino substituted by amonovalent aliphatic or araliphatic radical to introduce a furthermonovalent aliphatic or araliphatic radical.

Resulting salts may be converted in a manner known per se into the freecompounds, for example by treatment with a base, such as an alkali metalhydroxide, a metal carbonate or hydrogen carbonate, or with anothersalt-forming base mentioned at the beginning or with an acid, such as amineral acid, for example hydrochloric acid, or another salt-formingacid mentioned at the beginning.

Resulting salts may be converted in a manner known per se into differentsalts, for example acid addition salts may be converted by treatmentwith a suitable metal salt, such as a sodium, barium or silver salt, ofa different acid, in a suitable solvent in which an inorganic salt thatforms is insoluble and is thus eliminated from the reaction equilibrium,and basic salts may be converted into different salts by freeing thefree acid and converting into a salt again.

The compounds of formula I, including their salts, may also be obtainedin the form of hydrates, or may include the solvent used for theircrystallisation.

In view of the close relationship between the novel compounds in freeform and in the form of their salts, hereinbefore and hereinafter anyreference to the free compounds and their salts should be understood asincluding optionally also the corresponding salts and free compounds,respectively, as appropriate and expedient.

Resulting mixtures of diastereoisomers and mixtures of racemates can beseparated in known manner into the pure diastereoisomers and racemateson the basis of the physicochemical differences between theconstituents, for example by chromatography and/or fractionalcrystallisation. Resulting racemates can also be separated into theoptical antipodes by known methods, for example by recrystallisationfrom an optically active solvent, with the aid of microorganisms or byreaction of the resulting mixture of diastereoisomers or racemate withan optically active auxiliary compound, for example according to theacidic, basic or functionally modifiable groups present in compounds offormula I with an optically active acid, base or an optically activealcohol, to form mixtures of diastereoisomeric salts or functionalderivatives, such as esters, and separation thereof into thediastereoisomers from which the desired enantiomer can be freed in theappropriate customary manner. Examples of suitable bases, acids andalcohols are optically active alkaloid bases, such as strychnine,cinchonine or brucine, or D- or L-(1-phenyl)ethylamine, 3-pipecoline,ephedrine, amphetamine and similar synthetically obtainable bases,optically active carboxylic or sulfonic acids, such as quinic acid or D-or L-tartaric acid, D- or L-di-o-toluoyltartaric acid, D- or L-malicacid, D- or L-mandelic acid or D- or L-camphorsulfonic acid, oroptically active alcohols, such as borneol or D- or L-(1-phenyl)ethanol.

The invention relates also to those forms of the process in which acompound obtainable as intermediate at any stage of the process is usedas starting material and the remaining steps are carried out, or inwhich a starting material is used in the form of a salt or, especially,is formed under the reaction conditions.

The invention relates also to the novel starting materials developedspecifically for the preparation of the compounds of the invention,especially to those starting materials resulting in the compounds offormula I that were described at the beginning as being preferred, toprocesses for the preparation thereof and to their use as intermediates.

This relates, for example, to amides of formula IV wherein alk' isω-oxo-lower alkyl bonded to the group R in the ω-position, especiallycarbonyl, and to salts thereof as well as to processes for thepreparation thereof.

The invention accordingly relates also to novel compounds of formula IVa##STR10## wherein R is an amino group that is unsubstituted or mono- ordi-substituted by monovalent aliphatic and/or araliphatic radicals ordisubstituted by divalent aliphatic radicals and

R₁, R₂, R₃ and R₄ are each, independently of the others, hydrogen, loweralkyl, lower alkoxy, halogen or trifluoromethyl

and to salts thereof as well as to processes for the preparationthereof.

The invention relates preferably to those compounds of formula IVaresulting in the compounds of formula I that were described at thebeginning as being preferred, and to salts thereof as well as toprocesses for the preparation thereof.

The process for the preparation of novel compounds of formula IVacomprises reacting a compound of formula IX ##STR11## wherein R, R₁, R₂,R₃ and R₄ are as defined hereinbefore, with an amine of formula III

    Y--R                                                       (III),

wherein Y is free or temporarily protected amino, to form thecorresponding amide, removing again the amino-protecting group that mayhave been temporarily introduced and, if desired, in each caseconverting a compound obtainable in accordance with the process into adifferent compound of formula I, separating a mixture of isomersobtainable in accordance with the process into its components andisolating the desired isomer and/or converting a salt obtainable inaccordance with the process into the free compound or a free compoundobtainable in accordance with the process into a salt.

The reaction of compounds of formula IVa to form the correspondingamides is carried out in customary manner, for example by treatment withan acid halogenating agent, such as oxalyl chloride in the presence ofdimethylformamide.

The invention also relates preferably to pharmaceutical compositionscomprising the compounds of formula I according to the invention orpharmaceutically acceptable salts thereof as active ingredients, and toprocesses for the preparation thereof.

The pharmaceutical compositions according to the invention, whichcomprise a compound according to the invention or a pharmaceuticallyacceptable salt thereof, are pharmaceutical compositions for enteral,such as oral or rectal, and parenteral administration to warm-bloodedanimal(s) that comprise the pharmacological active ingredient alone ortogether with a pharmaceutically acceptable carrier. The daily dose ofthe active ingredient depends on the age and the individual condition aswell as on the mode of administration.

The novel pharmaceutical compositions comprise, for example, fromapproximately 10% to approximately 80%, preferably from approximately20% to approximately 60%, active ingredient. Pharmaceutical compositionsaccording to the invention for enteral or parenteral administration are,for example, in unit dose form such as in the form of dragees, tablets,capsules or suppositories, and also ampoules. They are prepared in amanner known per se, for example by means of conventional mixing,granulating, confectioning, dissolving or lyophilising processes. Forexample, pharmaceutical compositions for oral administration can beobtained by combining the active ingredient with solid carriers, ifdesired granulating a resulting mixture, and processing the mixture orgranules, if desired or necessary, after the addition of appropriateexcipients, into tablets or dragee cores.

Suitable carriers are especially fillers, such as sugars, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, and also binders, such as starch pastes using, for example,corn, wheat, rice or potato starch, gelatin, tragacanth,methyl-cellulose and/or polyvinylpyrrolidone, if desired disintegrators,such as the above-mentioned starches, also carboxymethyl starch,crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof,such as sodium alginate. Excipients are especially flow agents, flowconditioners and lubricants, for example silicic acid, talc, stearicacid or salts thereof, such as magnesium or calcium stearate, and/orpolyethylene glycol. Dragee cores are provided with suitable, optionallyenteric, coatings, there being used, inter alia, concentrated sugarsolutions which may comprise gum arabic, talc, polyvinylpyrrolidone,polyethylene glycol and/or titanium dioxide, or coating solutions insuitable organic solvents or solvent mixtures, or, for the preparationof enteric coatings, solutions of suitable cellulose preparations, suchas acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.Dyes or pigments may be added to the tablets or dragee coatings, forexample for identification purposes or to indicate different doses ofactive ingredient.

Other orally administrable pharmaceutical compositions are hard gelatincapsules and also soft, sealed capsules made of gelatin and aplasticiser, such as glycerol or sorbitol. The hard gelatin capsules maycomprise the active ingredient in the form of granules, for example inadmixture with fillers, such as lactose, binders, such as starches,and/or glidants, such as talc or magnesium stearate, and if desired withstabilisers. In soft capsules the active ingredients is preferablydissolved or suspended in suitable liquids, such as fatty oils, paraffinoil or liquid polyethylene glycols, it likewise being possible forstabilisers to be added.

Suitable rectally administrable pharmaceutical compositions are, forexample, suppositories that consist of a combination of the activeingredient with a suppository base material. Suitable suppository basematerials are, for example, natural or synthetic triglycerides, paraffinhydrocarbons, polyethylene glycols or higher alkanols. Gelatin rectalcapsules that comprise a combination of the active ingredient with abase material may also be used. Suitable base materials include, forexample, liquid triglycerides, polyethylene glycols and paraffinhydrocarbons.

There are suitable for parenteral administration by infusion and/orinjection especially aqueous solutions of an active ingredient inwater-soluble form, for example in the form of a water-soluble salt, andalso suspensions of the active ingredient, such as corresponding oilysuspensions, there being used suitable lipophilic solvents or vehicles,such as fatty oils, for example sesame oil, or synthetic fatty acidesters, for example ethyl oleate or triglycerides, or aqueoussuspensions that comprise viscosity-increasing substances, for examplesodium carboxymethylcellulose, sorbitol and/or dextran, and optionallyalso stabilisers.

The dosage of the active ingredient depends on the species ofwarm-blooded animal, the age and the individual condition and also onthe mode of administration. Normally the estimated approximate dailydose in the case of oral administration to a patient weighingapproximately 75 kg is from approximately 10 mg to approximately 500 mg.

The following Examples serve to illustrate the invention; temperaturesare given in degrees Celsius and pressures in mbar.

EXAMPLE 1 N-(Dibenz b,f!oxepin-10-ylmethyl-N-methyl-N-prop-2-ynylamine

Methylpropargylamine (4.5 g, 65 mmol) is dissolved in benzene (75 ml)and methanol (25 ml). At 40° C. a solution of 10-bromomethyldibenzb,f!oxepine (7.0 g, 25 mmol) in benzene (25 ml) is added dropwise in thecourse of half an hour. When the addition is complete, the mixture isstirred for a further half hour at 40°-50° C., poured into water, washedthree times with water and then extracted with 5% methanesulfonic acid.The acidic aqueous phase is rendered basic with concentrated ammonia andextracted with diethyl ether. The ethereal phase is dried over sodiumsulfate and concentrated by evaporation. Crystallisation of the residuefrom petroleum ether yields N-(dibenzb,f!oxepin-10-ylmethyl-N-methyl-N-prop-2-ynylamine alias10-(N-propargyl-N-methyl-amino)methyldibenz b,f!oxepine (5.3 g, 77%).Melting point: 66°-67° C.

EXAMPLE 2 N-Allyl-N-(dibenz b,f!oxepin-10-ylmethyl)amine hydrochloride

At 50° C. a solution of 0.5 ml (1.74 mmol) of 10-bromomethyl-dibenzb,F!oxepine is squirted into a solution of 0.3 ml (4 mmol) of allylaminein 0.9 ml of anhydrous methanol and the mixture is stirred for 30minutes. Tert-butyl methyl ether and ethyl acetate are added and themixture is extracted 3× with 20 ml of 1N hydrochloric acid each time,the combined aqueous phases are rendered basic with potassium hydroxidepellets and extracted 2× with ethyl acetate, and the organic phases aredried over sodium sulfate and concentrated. 0.35 ml (0.7 mmol) of 2Nethereal hydrochloric acid is added to the crude amine (180 mg) in 2 mlof diethyl ether, and the precipitated white hydrochloride is washedwith diethyl ether and dried under a high vacuum at 40° C. 200 mg (667μmol)=39% of the title compound alias 10-allylaminomethyl-dibenzb,f!oxepine are obtained in the form of white crystals; melting point:148°-158° C.; ¹ H-NMr (CD₃ OD, 200 MHz). 3.74 (d, 2H); 4.35 (d, 2H),5.55 (m, 2H); 5.95 (m, 1H); 7.20-7.58 (m, 9H); MS: 263 (M⁺, free base),222, 208, 181, 165, 152.

EXAMPLE 3 N-Allyl-N-(dibenz b,f!oxepin-10-ylmethyl)N-methylaminehydrochloride

Preparation analogous to Example 2 from 10-bromomethyl-dibenzb,f!oxepine and N-methyl-allylamine Yield: 71%; melting point: 153°-156°C.; ¹ H-NMR (CD₃ OD, 200 MHz): 2.85 (s, 3H); 3.86 (d, 2H); 4.50 (sbr,2H); 5.60 (d, 1H); 5.68 (s, 1H); 6.00 (m, 9H); (m, 1H); 7.20-7.60 MS:277 (M⁺, free base), 208, 181, 152.

EXAMPLE 4 N-(Dibenz b,f!oxepin-10-ylmethyl-N-methyl-N-prop-2-ynylamine

Preparation analogous to Example 2 from 10-bromomethyl-dibenzb,f!oxepine and N-methyl-N-propargylamine, as free base, chromatographedon silica gel with hexane/ethyl acetate=4:1 and crystallised from asmall amount of petroleum ether. Yield: 74%; melting point: 67°-68° C.;¹ H-NMR (CDCl₃, 300 MHz): 2.30 (d, 1H); 2.42 (s, 3H); 3.48 (t, 2H) 3.65(s, 2H); 6.90 (d, 1H); 7.08-7.36 (m, 7H); 7.56 (m, 1H); MS: 275 (M⁺),232, 208, 181, 165, 152; analysis: C 82.77% (82.88), H 6.18% (6.22); N4.99% (5.09).

The title compound is identical to the product according to Example 1.

EXAMPLE 5 N-(Dibenz b,f!oxepin-10-ylmethyl-N-methyl-N-prop-2-ynylamineoxalate

Preparation analogous to Example 2; oxalate salt from free base withoxalic acid in ethanol. Melting point: 202°-205° C.; analysis: C 68.79%(69.03); H 5.29% (5.24); N 3.86% (3.83).

EXAMPLE 6 N-(Dibenz b,f!oxepin-10-ylmethyl)amine (in the form of thehydrochloride)

1.0 g (3.48 mmol) of 10-bromomethyl-dibenz b,f!oxepine in 3 ml oftoluene is added dropwise at 40° C. to 30 ml of NH₃ -saturated methanoland the mixture is stirred at 35°-50° C. for 1 hour and at roomtemperature overnight. The solvent is partially removed, and thereaction mixture is taken up in tert-butyl methyl ether, washed with0.1N sodium hydroxide solution and extracted with 1N hydrochloric acid.The aqueous phase is rendered basic with sodium hydroxide pellets andextracted with tert-butyl methyl ether, the organic phase is dried oversodium sulfate and the solvent is removed. 349 mg (1.56 mmol)=45% ofN-(dibenz b,f!oxepin-10-ylmethyl)amine are obtained in the form of alight-yellow oil; TLC (silica gel, ethyl acetate; UV): R_(f) =0.09.

EXAMPLE 7 N-(Dibenz b,f!oxepin-10-ylmethyl)-N-prop-2-ynylaminehydrochloride

A mixture of 1.1 g (3.044 mmol) of N-(dibenzb,f!oxepin-10-ylmethyl-prop-2-ynyl-carbamic acid tert-butyl ester and1.45 ml of methanesulfonic acid in 1 ml of dioxane and 9 ml ofdichloromethane is stirred for 1hour at room temperature, 2N sodiumhydroxide solution is added and the mixture is extracted 2× withdichloromethane. The organic phase is concentrated using a rotaryevaporator, taken up in ethyl acetate and extracted 3× with 1Nhydrochloric acid, and the aqueous phase is rendered basic withpotassium hydroxide pellets, extracted 3× with dichloromethane, driedover sodium sulfate and concentrated. The crude light-brown oil isdissolved in 2N ethereal hydrochloric acid and concentrated. The crudehydrochloride (beige crystals) is recrystallised from ethylacetate/methanol. 386 mg (1.30 mmol)=42% of N-(dibenzb,f!oxepin-10-ylmethyl)-N-prop-2-ynylamine hydrochloride alias10-propargylaminomethyldibenz b,f!oxepine hydrochloride are obtained inthe form of white crystals; melting point: 181°-183° C.; MS: 261 (M⁺,free base), 222, 181, 165, 152.

The starting material can be prepared, for example, in the followingmanner:

a) Dibenz b,f!oxepin-10-ylmethyl-carbamic acid tert-butyl ester

2.25 g (10.3 mmol) of di-tert-butyl dicarbonate (BOC)₂ O are added atroom temperature to a solution of 2.3 g (10.3 mmol) of N-(dibenzb,f!oxepin-10-ylmethyl)amine in 20 ml of dichloromethane, and themixture is stirred for 30 minutes and freed of solvent using a rotaryevaporator. 3.61 g of dibenz b,f!oxepin-10-ylmethyl-carbamic acidtert-butyl ester are obtained in the form of a crude yellow oil whichbecomes solid on being left to stand. TLC (silica gel; ethylacetate/hexane=9:1; UV): R_(f) =0.36.

b) Dibenz b,f!oxepin-10-ylmethyl-prop-2-ynyl-carbamic acid tert-butylester

1.0 g (3.091 mmol) of dibenz b,f!oxepin-10-ylmethyl-carbamic acidtert-butyl ester is placed in 10 ml of dimethylformamide, 0.22 g (4.636mmol) of 55% sodium hydride suspension (in oil) is added at roomtemperature, the mixture is stirred for 15 minutes and then 0.279 ml(3.709 mmol) of propargyl bromide is added dropwise at room temperature.After 1 hour, water and a small amount of brine are carefully added andtert-butyl methyl ether is mixed in. The organic phase is washed 4× withwater, dried over sodium sulfate and concentrated. 1.106 g (3.06mmol)=98.8% of dibenz b,f!oxepin-10-ylmethyl-prop-2-ynyl-carbamic acidtert-butyl ester are obtained in the form of a brown oil. TLC (silicagel, ethyl acetate/hexane=9:1; UV): R_(f) =0.45.

EXAMPLE 8 N-(Dibenz b,f!oxepin-10-ylmethyl)-N-propylamine hydrochloride

Preparation analogous to Example 2 from 10-bromomethyl-dibenzb,f!oxepine and propylamine; yield: 19%; melting point: 142°-152° C.; ¹H-NMR (CD₃ OD, 200 MHz): 1.01 (t, 3H); 1.76 (m, 2H); 3.03 (m, 2H); 4.25(s, 2H); 7.19-7.69 (m, 10H); MS: 265 (M⁺, free base), 222, 207, 181

EXAMPLE 9 N-(Dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-propylaminetosylate

Preparation analogous to Example 2 from 10-bromomethyl-dibenzb,f!oxepine and N-methyl-N-propylamine. Tosylate prepared with 1equivalent of p-toluenesulfonic acid in ethyl acetate, crystallised fromdichloromethane/tert-butyl methyl ether. Yield: 68%; melting point:179°-180° C.; ¹ H-NMR (CD₃ OD, 200 MHz): 0.97 (t, 3H); 1.78 (m, 2H);2.36 (s, 3H); 2.85 (s, 3H); 3.15 (mbr, 2H); 4.50 (mbr, 2H); 7.17°-7.75(m, ca. 13H); MS: 279 (M⁺, free base), 250, 207.

EXAMPLE 10 1 Dibenz b,f!oxepin-10-ylmethyl-piperidine hydrochloride

A solution of 1.954 g (6.395 mmol) of dibenzb,f!oxepin-10-yl-piperidin-1-yl-methanone in 5 ml of tetrahydrofuran isadded dropwise at 0° C. to a suspension of 365 mg (9.59 mmol) of lithiumaluminium hydride in 15 ml of tetrahydrofuran and the mixture is thenstirred at room temperature overnight. The mixture is hydrolysed with0.37 ml of water, 4N sodium hydroxide and 1.11 ml of water, filtered,and the filtrate is extracted with ethyl acetate. The resulting greenishoil is converted with ethereal hydrochloric acid into the hydrochloridewhich is recrystallised from hexane and a very small amount oftert-butyl methyl ether to yield 1.29 g (3.93 mmol)=61% of 1-dibenzb,f!oxepin-10-ylmethyl-piperidine hydrochloride in the form of whitecrystals; melting point: 172°-173° C.; ¹ H-NMR (CD₃ OD, 200 MHz):1.40-2.00 (mbr, 6H); 3.00 (tbr, 2H); 3.52 (dbr, 2H); 4.47 (s, 2H);7.26-7.63 (m, 9H); MS: 291 (M⁺, free base), 208, 181, 152.

The starting material can be prepared, for example, in the followingmanner:

a) Dibenz b,f!oxepin-10-yl-piperidin-1-yl-methanone 1.1 ml (12.59 mmol)of oxalyl chloride and 1drop of dimethylformamide are added at roomtemperature to a solution of 3.0 g (12.59 mmol) of dibenzb,f!oxepine-10-carboxylic acid in 20 ml of dichloromethane and themixture is stirred for 4 hours. 1.86 ml (18.88 mmol) of piperidine and2.62 ml (18.88 mmol) of Et₃ N are then added and the mixture is stirredat room temperature overnight. The reaction mixture is washed 1× withhydrochloric acid and brine, and the organic phase is dried,concentrated, subjected to column chromatography and crystallised fromtert-butyl methyl ether. 2.64 g (8.6 mmol)=69% of dibenzb,f!oxepin-10-yl-piperidin-1-yl-methanone are obtained in the form oflight-yellow crystals; melting point: 127°-128° C.; ¹ H-NMR (CDCl₃, 200MHz): 1.30-1.50 (mbr, 2H); 1.50-1.70 (mbr, 4H); 3.30-3.45 (mbr, 2H);3.63-3.78 (mbr, 2H); 6.92 (s, 1H); 7.10-7.40 (m, 8H); MS: 305 (M⁺), 221,193, 165; TLC (silica gel; ethyl acetate/hexane=1:1; UV): R_(f) =0.32.

EXAMPLE 11 4-Dibenz b,f!oxepin-10-ylmethyl-morpholine hydrochloride

Preparation analogous to Example 10 from dibenzb,f!oxepin-10-yl-morpholin-4-yl-methanone; yield: 62%; white crystals;melting point: 213°-215° C.; ¹ H-NMR (CDCl₃, 300 MHz): 2.95 (m, 2H);3.32 (m(d), 2H); 3.90 (m(d), 2H); 4.25 (t, 2H); 4.40 (s, 2H); 7.11-7.45(m, 9H). MS:293 (M⁺, free base), 208, 181, 152.

The starting material can be prepared, for example, in the followingmanner:

a) Dibenz b,f!oxepin-10-yl-morpholin-4-yl-methanone

Preparation analogous to Example 10a from dibenzb,f!oxepine-10-carboxylic acid and morpholine; yield: 62%; yellow oil; ¹H-NMR (CDCl₃, 200 MHz): 3.30 (mbr, 4H); 3.62 (mbr, 4H); 6.90-7.28 (m,9H); MS: 307 (M⁺), 221, 193, 165; TLC (silica gel; ethylacetate/hexane=1:1; UV): R_(f) =0.17.

EXAMPLE 12 N-(1-Chloro-dibenzb,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine hydrochloride

Preparation analogous to Example 2 from 10-bromomethyl-1-chlorodibenzb,f!oxepine with N-methyl-N-propargylamine. Yield: 75%; melting point:not determined, (white foam); ¹ H-NMR (CDCl₃, 200 MHz): 2.35 (t, 1H);2.45 (s, 3H); 3.51 (d, 2H); 3.70 (s, 2H); 7.10-7.40 (m, 7H); 7.61 (m,1H).

The starting material can be prepared, for example, in the followingmanner:

a) 2-Chloro-6-phenoxy-benzaldehyde

A mixture of 15.8 g (100 mmol) of 2-chloro-6-fluorobenzaldehyde, 9.4 g(100 mmol) of phenol and 20.7 g (150 mmol) of potassium carbonate in 150ml of dimethylacetamide is heated under reflux for 4 hours The mixtureis allowed to cool, water is added and the mixture is extracted 3× withtert-butyl methyl ether. The organic phases are washed with 2N sodiumhydroxide solution and brine, dried over sodium sulfate andconcentrated. Bulb tube distillation (175° C., 0.04 mbar) yields 19.46 g(83.64 mmol)=83.6% of 2-chloro-6-phenoxy-benzaldehyde in the form of ayellow oil, ¹ H-NMR (CDCl₃, 200 MHz): 6.75-7.45 (m, 8H); 10.58 (s, 1H).

b) (2-Chloro-6-phenoxy-phenyl)methanol

19.0 g (77.67 mmol) of 2-chloro-6-phenoxybenzaldehyde in approximately40 ml of tetrahydrofuran are added dropwise at room temperature in thecourse of 30 minutes to a suspension of 4.42 g (116.5 mmol) of lithiumaluminium hydride in approximately 150 ml of tetrahydrofuran. Themixture is then heated under reflux for 4 hours, cooled and hydrolysedwith 4.4 ml of water, 4.4 ml of 4N sodium hydroxide and 13.2 ml ofwater. The reaction mixture is boiled under reflux for 30 minutes,cooled and filtered, and the suction filter residue is 3× taken up inethyl acetate, boiled under reflux for 15 minutes and filtered. Thecombined filtrates are concentrated. 17.97 g (76.57 mmol)=94% of crude(2-chloro-6-phenoxy-phenyl)-methanol are obtained in the form of ayellow oil; TLC (silica gel; ethyl acetate/hexane=1:1; UV): R_(f) =0.68;¹ H-NMR (CDCl₃, 200 MHz): 4.90 (s, 2H); 6.76-7.40 (m, 8H).

c) (2-Chloro-6-phenoxy-phenyl)-bromomethane

17.5 g (70.94 mmol) of (2-chloro-6-phenoxy-phenyl)-methanol are heatedunder reflux for 3 hours in 150 ml of 8% hydrobromic acid. The mixtureis cooled, water is added and the mixture is extracted 3× with ethylacetate. The organic phases are washed with brine, dried over sodiumsulfate and concentrated. 21.21 g (>100%) of crude(2-chloro-6-phenoxy-phenyl)-bromomethane are obtained in the form of ayellow oil; TLC (silica gel; ethyl acetate/hexane=1:1; UV): R_(f) =0.70;¹ H-NMR (CDCl₃, 200 MHz): 4.78 (s, 2H); 6.70-7.41 (m, 8H).

d) (2-Chloro-6-phenoxy-phenyl)acetonitrile

A solution of 21.0 g (70.57 mmol) of(2-chloro-6-phenoxy-phenyl)-bromomethane in 16.5 ml of ethanol is addeddropwise at 80° C. to a solution of 4.5 g (91.74 mmol) of sodium cyanidein 9.2 ml of water and 2.3 ml of ethanol and the reaction mixture isboiled under reflux for 4 hours. After cooling, the mixture isconcentrated using a rotary evaporator, the residue is taken up in ethylacetate and the organic phase is washed 2× with water and 1× with brine,dried over sodium sulfate, concentrated and chromatographed on silicagel with ethyl acetate to yield 10.82 g (44.40 mmol)=63% of(2-chloro-6-phenoxyphenyl)-acetonitrile in the form of a brown oil; TLC(silica gel; ethyl acetate; UV): R_(f) =0.42; ¹ H-NMR (CDCl₃, 200 MHz):3.96 (s, 2H); 6.74-7.46 (m, 8H)

e) 1-Chloro-dibenz b,f!oxepine-10-carboxylic acid

10.82 g (44.40 mmol) of (2-chloro-6-phenoxy-phenyl)-acetonitrile and7.85 g (53.72 mmol) of oxalic acid diethyl ester are added at roomtemperature to a freshly prepared sodium ethanolate solution (1.5 g(53.72 mmol) of sodium in 50 ml of ethanol) and the mixture is stirredfor 18 hours. The mixture is rendered acidic with 1N hydrochloric acid,concentrated using a rotary evaporator and extracted 2× with ethylacetate, and the organic phase is washed with brine, dried over sodiumsulfate and concentrated to yield 15.99 g of crude intermediate(3-(2-chloro-6-phenoxy-phenyl)-2-hydroxy-4-nitrilo-but-2-enoic acidethyl ester) 15.0 g (approximately 43.6 mmol) of the above intermediateare placed in 105 ml of glacial acetic acid and stirred for 20 minutes,51.9 ml of water and 51.9 ml of sulfuric acid are slowly added, and themixture is heated for 4 hours under reflux and then for 18 hours at roomtemperature. The reaction mixture is extracted with ethyl acetate, theorganic phase is washed with water and 3× with 4N sodium hydroxide, andthe aqueous phase is extracted 1× with ethyl acetate. The aqueous phasesare rendered acidic with concentrated hydrochloric acid and extracted 3×with ethyl acetate, and the organic phase is dried over sodium sulfateand concentrated. 7.71 g (28.27 mmol)=60.3% of 1-chloro-dibenzb,f!oxepine-10-carboxylic acid are obtained in the form of a yellowsolid; TLC (silica gel; ethyl acetate/hexane=1:1; UV): R_(f) =0.21; ¹H-NMR (CDCl₃, 200 MHz): 7.15-7.47 (m, 7H); 7.68 (m, 1H), 8.39 (s, 1H).

f) (1-Chloro-dibenz b,f!oxepin-10-yl)methanol

2.0 ml (18.33 mmol) of N-methylmorpholine and 2.4 ml (18.33 mmol) ofisobutyl chloroformate are added dropwise at -15° C. to a solution of5.0 g (18.33 mmol) of 1-chloro-dibenz b,f!oxepine-10-carboxylic acid indimethoxyethane. After 5 minutes filtration is carried out and at -15°C. a solution of 1.39 g (36.67 mmol) of sodium borohydride in 15 ml ofwater is added dropwise to the filtrate. The mixture is stirred for 15minutes at -15° C., then 35 ml of 1N hydrochloric acid are added and themixture is allowed to warm to room temperature. The reaction mixture isrendered basic with sodium hydroxide and extracted 4× with ethylacetate. The organic phase is washed 1× with water, dried over sodiumsulfate and concentrated. 4.58 g (17.7 mmol)=96.6% of crude(1-chlorodibenz b,f!oxepin-10-yl)-methanol are obtained in the form of ayellow oil; TLC (silica gel; ethyl acetate/hexane=1:1; UV): R_(f)=10.46; ¹ H-NMR (CDCl₃, 200 MHz): 2.42 (sbr, 1H); 1H); 4.71 (s, 2H);7.10-7.45 (m, 7H).

g) 10-Bromomethyl-1-chloro-dibenz b,f!oxepine

4.58 g (17.70 mmol) of (1-chlorodibenz b,f!oxepin-10-yl)-methanol areheated under reflux in 50 ml of 48% hydrobromic acid for 2 hours. Themixture is cooled, water is added and the mixture is extracted 3× withethyl acetate. The organic phases are washed with brine, dried oversodium sulfate and concentrated. 5.57 g of crude product are obtainedwhich becomes solid on being left to stand (3 days). Recrystallisationfrom tert-butyl methyl ether/hexane yields 2.205 g (6.86 mmol)=38.7% of10-bromomethyl-1-chloro-dibenz b,f!oxepine in the form of light-beigecrystals; TLC (silica gel; ethyl acetate; UV): R_(f) =0.73; ¹ H-NMR(CDCl₃, 200 MHz): 4.60 (s, 2H); 7.15-7.58 (m, 8H).

EXAMPLE 13 1-(1-Chloro-dibenz b,f!oxepin-10-ylmethyl)-pyrrolidinehydrochloride

Preparation analogous to Example 2 from 10-bromomethyl-1-chloro-dibenzb,f!oxepine with pyrrolidine. Yield: 51%, yellow foam; melting point:not determined, (yellow foam); ¹ H-NMR (CDCl₃, 200 MHz): 1.78 (m, 4H);2.65 (m, 4H); 3.65 (s, 2H); 7.10-7.45 (m, 7H) 7.68 (d, 1H).

EXAMPLE 14 N-(1-Chloro-dibenzb,f!oxepin-10-ylmethyl)-N-methyl-N-propylamine hydrochloride

Preparation analogous to Example 2 from 10-bromomethyl-1-chlorodibenzb,f!oxepine with N-methyl-propylamine; yield: 25%; beige solid; meltingpoint: not determined, (beige foam); ¹ H-NMR (CDCl₃, 200 MHz): 0.88 (t,3H); 1.55 (m, 2H); 2.28 (s, 3H); 2.43 (t, 2H); 3.55 (s, 2H), 7.08-7.35(m, 7H); 7.61 (d, 1H).

EXAMPLE 15 N-Methyl-N-prop-2-ynyl-N-(3-trifluoromethyl-dibenz b,f!oxepin10-ylmethyl)amine

Preparation analogous to Example 2 from10bromomethyl-3-trifluoromethyldibenz b,f!oxepine andN-methyl-propargylamine. As free base chromatographed on silica gel withhexane/ethyl acetate=1:1 and crystalised from a small amount ofpetroleum ether; yield: 56%; melting point: 66°-68° C.; ¹ H-NMR (CDCl₃,200 MHz): 1.80 (t, 1H); 2.41 (s, 3H); 3.46 (d, 2H); 3.65 (s, 2H); 6.91(sbr, 1H); 7.15-7.58 (m, 7H); MS: 343 (M⁺), 342, 300, 276, 249, 205,178, 152.

The starting material can be prepared, for example, in the followingmanner:

a) 2-Phenoxy-4-trifluoromethyl-benzaldehyde

Preparation analogous to Example 12 from2-fluoro-4-trifluoromethyl-benzaldehyde and phenol. Yield: 78%,light-coloured crystals, crystallised from hexane; melting point:57°-59° C.; TLC (silica gel; ethyl acetate/hexane=1:1; UV): R_(f) =0.71;¹ H-NMR (CDCl₃, 200 MHz): 7.08-7.50 (m, 7H): 8.05 (d, 1H) 10.60 (s, 1H).MS: 266/265 (M⁺), 217, 188.

b) 3-Trifluoromethyl-dibenz b,f!oxepine-10-carboxylic acid

A mixture of 10.0 g (37.59 mmol) of2-phenoxy-4-trifluoromethyl-benzaldehyde, 10.09 g (56.40 mmol) ofhippuric acid and 3.70 g (45.10 mmol) of sodium acetate in 38 ml ofacetic anhydride is heated at 85° C. for 80 minutes, then cooled to 32°C. 19 ml of water are added and the mixture is heated at 65° C. for 30minutes. After cooling the mixture to approximately 5° C., 19 ml ofconcentrated sulfuric acid are added dropwise and the mixture is thenheated under reflux (bath: 140° C.) for 2 hours. The brown precipitatethat forms on cooling is filtered and washed with 50% acetic acid,washed with water until neutral and dried to yield 7.42 g (24.23mmol)=65% of 3-trifluoromethyl-dibenz b,f!oxepine-10-carboxylic acid inthe form of beige crystals; melting point: 180° C.; ¹ H-NMR (CDCl₃, 200MHz): 7.2-7.65 (m, 8H) 8.09 (s, 1H).

c) (3-Trifluoromethyl-dibenz b,f!oxepin-10-yl)-methanol

Preparation analogous to Example 12 f) from 3-trifluoromethyl-dibenzb,f!oxepine-10-carboxylic acid. Product crystallised from tert-butylmethyl ether/hexane; yield: 75.2%; white crystals: TLC (silica gel;ethyl acetate/hexane=1:1; UV): R_(f) =0.31; ¹ H-NMR (CDCl₃, 200 MHz):2.76 (sbr, 1H); 4.72 (s, 2H); 6.96 (s, 1H); 7.16-7.48 (m, 7H).

d) 10-Bromomethyl-3-trifluoromethyl-dibenz b,f!oxepine

Preparation analogous to Example 12 g) from (3-trifluoromethyl-dibenzb,f!oxepin-10-yl)-methanol. Product crystallised from hexane; yield:92%, white crystals; TLC (silica gel; ethyl acetate/hexane=1:1; UV):R_(f) =0.70; ¹ H-NMR (CDCl₃, 200 MHz): 4.55 (s, 2H); 7.04 (s, 1H);7.20-7.60 (m, 7H); MS: 356/354 (M⁺), 275, 249, 219, 206, 205, 178, 176.

EXAMPLE 16 1-(3-Trifluoromethyl-dibenzb,f!oxepin-10-ylmethyl)-pyrrolidine hydrochloride

Preparation analogous to Example 2 from10-bromomethyl-3-trifluoromethyldibenz b,f!oxepine and pyrrolidine.Yield: 86%; light-beige crystals; melting point:>220° C.; ¹ H-NMR (CD₃OD, 200 MHz): 1.90-2.20 (m, 4H); 2.25 (m, 2H); 3.55 (m, 2H); 4.59 (s,2H); 7.30-7.70 (m, 8H). MS: 345 (M⁺, free base), 276, 249, 205, 178,152.

EXAMPLE 17: N-(7-Chloro-dibenzb,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine hydrochloride

Preparation analogous to Example 2 from 10-bromomethyl-7-chlorodibenzb,f!oxepine and N-methyl-propargylamine. Yield: 68%; beige crystals;melting point: 189°-195°0 C.; ¹ H-NMR (CD₃ OD, 200 MHz): 2.96 (s, 3H);3.49 (m(t), 1H); 4.15 (m(d), 2H; 4.60 (sbr, 1H); 7.20-7.65 (m, 8H); MS:309 (M⁺, free base), 266, 244, 242, 241, 215, 205, 176, 163, 152.

The starting material can be prepared, for example, in the followingmanner:

a) 2-(3-Chlorophenoxy)benzaldehyde

Preparation analogous to Example 12 a) from 2-fluoro-benzaldehyde and3-chlorophenol. Yield: 69%; yellow oil after bulb tube distillation(150°-180° C., 0.001 torr); ¹ H-NMR (CDCl₃, 200 MHz): 6.92-7.38 (m, 6H);7.55 (m, 1H); 7.95 (m, 1H), 10.48 (s, 1H).

b) 7-Chloro-dibenz b,f!oxepine-10-carboxylic acid

Preparation analogous to Example 15 b) from2-(3-chlorophenoxy)-benzaldehyde. Crystallised from tert-butyl methylether/hexane. Yield: 25%; light-yellow crystals; TLC (silica gel; ethylacetate/hexane=1:1; UV): R_(f) =0.15; ¹ H-NMR (CDCl₃, 200 MHz):7.05-7.50 (m, 8H); 7.90 (s, 1H). MS: 274/272 (M⁺).

c) (7-Chloro-dibenz b,f!oxepin-10-yl)methanol

Preparation analogous to Example 12 f) aus 7-chloro-dibenzb,f!oxepine-10-carboxylic acid. Yield: 94% in the form of an oil; TLC(silica gel; ethyl acetate/hexane=1:1; UV): R_(f) =0.38; ¹ H-NMR (CDCl₃,200 MHz) 1.72 (sbr, 1H); 4.67 (s, 2H); 6.91 (s, 1H); 7.10-7.40 (m, 7H);MS: 260/258 (M⁺), 217/215.

d) 10-Bromomethyl-7-chloro-dibenz b,f!oxepine

Preparation analogous to Example 12 g) from (7-chloro-dibenzb,f!oxepin-10-yl)-methanol. Product crystallised from hexane. Yield:56%; almost white crystals; melting point: 117°-119° C.; TLC (silicagel; ethyl acetate/hexane=1:1; UV): R_(f) =0.70; ¹ H-NMR (CDCl₃, 200MHz): 4.51 (s, 2H); 7.03 (s, 1H); 7.24-7.50 (m, 7H) ; MS: 324/322/320(M⁺, Br-Cl-isotope distribution), 243/241 (Cl-isotope distribution),206/205, 178/176.

EXAMPLE 18 1-(7-Chloro-dibenz b,f!oxepin-10-ylmethyl)-pyrrolidinehydrochloride

Preparation analogous to Example 2 from 10-bromomethyl-7-chloro-dibenzb,f!oxepine and pyrrolidine. Yield: 5%, melting point:>225° C.decomposition. ¹ H-NMR (CD₃ OD, 200 MHz): 1.95-2.20 (m, 4H); 3.25 (m2H); 3.55 (m, 2H), 4.52 (s, 2H), 7.20-7.45 (m, 7H); 7.60 (d, 1H). MS:311 (M⁺, free base), 244, 242, 241, 215, 205, 178, 176, 163, 152.

EXAMPLE 19 N-(8-Methoxy-dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine hydrochloride

Preparation analogous to Example 2 from 10-bromomethyl-8-methoxy-dibenzb,f!oxepine and N-methyl-propargylamine. Yield: 35%, white crystals;melting point: decomposition>60° C. ¹ H-NMR (CDCl₃, 200 MHz): 2.33 (t,1H); 2.42 (s, 3H); 3.48 (d, 2H); 3.62 (s, 2H); 3.78 (s, 3H); 6.80-6.90(m, 2H); 7.05-7.32 (m, 6H).

The starting material can be prepared, for example, in the followingmanner:

a) 8-Methoxy-dibenz b,f!oxepine-10-carboxylic acid

Preparation analogous to Example 15 b) from2-(4-methoxy-phenoxy)-benzaldehyde. Silica gel chromatography (eluant:ethyl acetate/hexane=1:1), then crystallisation from ethylacetate/hexane=7:3. Yield: 19%, beige crystals; melting point: 150° C.;TLC (silica gel; ethyl acetate/hexane=1:1; UV): R_(f) =0.58; ¹ H-NMR(CDCl₃, 200 MHz): 3.80 (s, 3H); 6.92 (dd, 1H); 7.17-7.45 (m, 7H); 8.13(s, 1H); MS: 268 (M⁺).

b) (8-Methoxy-dibenz b,f!oxepin-10-yl)methanol

Preparation analogous to Example 12 f) from 8-methoxy-dibenzb,f!oxepine-10-carboxylic acid. Yield: 96% in the form of a brown oil;TLC (silica gel; ethyl acetate/hexane=1:1; UV): R_(f) =0.31; ¹ H-NMR(CDCl₃, 300 MHz): 1.80 (sbr, 1H); 3.78 (s, 3H); 4.69 (s, 2H); 6.82-7.33(m, 8H); MS: 254 (M⁺), 211, 182, 181 168, 165. 153, 152.

c) 10-Bromomethyl-8-methoxy-dibenz b,f!oxepine

Preparation analogous to Example 12 g) from (8-methoxy-dibenzb,f!oxepin-10-yl)-methanol. Product crystallised from hexane/tertbutylmethyl ether. Yield: 96%, light-brown crystals: TLC (silica gel, ethylacetate; UV): R_(f) =0.70, ¹ H-NMR (CDCl₃, 200 MHz): 3.80 (s, 3H ); 4.52(s, 2H ); 6.86-7.37 (m, 8H).

EXAMPLE 20 N-(8-Tert-butyl-dibenzb,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine hydrochloride

Preparation analogous to Example 2 from 10-bromomethyl-tert-butyldibenzb,f!oxepine and N-methyl-propargylamine. Yield: 24%, beige crystals;melting point: 135°-145° C.; ¹ H-NMR (CD₃ OD, 200 MHz): 1.35 (s, 9H);2.96 (s, 3H); 3.52 (t, 1H); 4.17 (d, 2H), 7.15-7.60 (m, 9H); EI-MS:331(M⁺), 264, 249, 237, 207.

The starting material can be prepared, for example, in the followingmanner:

a) 2-(4-Tert-butyl-phenoxy)benzaldehyde

Preparation analogous to Example 12 a) from 2-fluoro-benzaldehyde and4-tert-butylphenol. Yield: 77%, yellow oil after high vacuumdistillation (93°-100° C., 0.9 mbar); TLC (silica gel; hexane/ethylacetate=1:1; UV): R_(f) =0.65; ¹ H-NMR (CDCl₃, 200 MHz): 1.35 (s, 9H);6.75-7.55 (m, 7H); 7.92 (dd, 1H); 10.50 (s, 1H); MS: 254 (M⁺), 239.

b) 8-Tert-butyl-dibenz b,f!oxepine-10-carboxylic acid

Preparation analogous to Example 15 b) from2-(4-tert-butyl-phenoxy)-benzaldehyde. Crystallised from hexane. Yield:16%, light-yellow crystals; melting point: 72° C.; TLC (silica gel;hexane/ethyl acetate=4:1; UV): R_(f) =0.46, ¹ H-NMR (CDCl₃, 200 MHz):1.31 (s, 9H); 7.15-7.45 (m, 8H); 7.62 (d, 1H); 8.10 (s, 1H); MS: 295(M⁺), 279, 239.

c) (8-Tert-butyl-dibenz b,f!oxepin-10-yl)methanol

Preparation analogous to Example 12 f from 8-methoxy-dibenzb,f!oxepine-10-carboxylic acid. Yield: 30% in the form of an oil afterchromatography (silica gel; hexane/ethyl acetate=9:1) and bulb tubedistillation (100° C., 0.3 mbar) ; TLC (silica gel; hexane/ethylacetate=9:1; UV): R_(f) =0.11. ¹ H-NMR (CDCl₃, 200 MHz): 1.30 (s, 9H);1.72 (sbr, 1H); 4.75 (s, 2H); 6.92 (s, 1H); 7.06-7.45 (m, 7H); MS: 280(M⁺), 265, 237.

d) 10-Bromomethyl-8-tert-butyl-dibenz b,f!oxepine

Preparation analogous to Example 12 g) from (8-tert-butyl-dibenzb,f!oxepin-10-yl)-methanol. Yield: 85%, brown oil; TLC (silica gel;ethyl acetate/hexane=1:1; UV): R_(f) =0.58, hu 1H-NMR (CDCl₃, 200 MHz):1.31 (s, 9H); 4.58 (s, 2H), 7.05-7.45 (m, 7H); 7.60 (d, 1H); MS: 344/342(M⁺), 263.

EXAMPLE 21 1-(8-Tert-butyl-dibenz b,f!oxepin-10-ylmethyl)-pyrrolidinehydrochloride

Preparation analogous to Example 2 from10-bromomethyl-8-tert-butyl-dibenz b,f!oxepine (see above) andpyrrolidine. Yield: 6%, yellow crystals; melting point: 184°-185° C.; ¹H-NMR (CD₃ OD, 200 MHz): 1.48 (s, 9H); 1.95-2.22 (mbr, 4H); 3.25 (mbr,2H); 3.53 (mbr, 2H); 4.57 (s, 2H); 7.18-7.58 (m, 8H) ; MS: 333 (M⁺, freebase), 264, 249, 237, 207.

EXAMPLE 22 N-(6-Chloro-dibenzb,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine hydrochloride

Preparation analogous to Example 2 from 10-bromomethyl-6-bromodibenzb,f!oxepine and N-methyl-propargylamine. Yield: 14%, white crystals;melting point: 188°-190° C.; ¹ H-NMR (free base) (CDCl₃, 200 MHz): 2 28(t, 1H); 2.40 (s, 3H); 3.45 (d, 2H); 3.63 (s, 2H); 6.93-7.50 (m, 8H) ;MS: 310, 312 (M⁺ +1, free base).

The starting material can be prepared, for example, in the followingmanner:

a) 2-(2-Chlorophenoxy)phenyl!methanol

Preparation analogous to Example 12 b) from 2-(2-chlorophenoxy)-benzoicacid distilled under a high vacuum. Yield: 53%, yellow oil; TLC (silicagel; ethyl acetate) R_(f) =0.74; ¹ H-NMR (CDCl₃, 200 MHz): 2.60 (sbr,1H), 4.78 (s, 2H); 6.70-7.50 (m, 8H). FD-MS: 234, 236 (M⁺).

b) 2-(2-Chlorophenoxy)-phenyl!-bromomethane

Preparation analogous to Example 12 c) from2-(2-chlorophenoxy)-phenyl!-methanol. Crystallised from hexane. Yield.97% crude, slightly brownish oil; ¹ H-NMR (CDCl₃, 200 MHz): 4.68 (s,2H); 6.70 (dd, 1H); 7.02-7.52 (m, 7H) ; TLC (silica gel; hexane/ethylacetate=7:3; UV): R_(f) =0.69.

c) 2-(2-Chlorophenoxy)-phenyl!acetonitrile

Preparation analogous to Example 12 d) from2-(2-chlorophenoxy)-phenyl!-bromomethane. Yield: 99%, crude, brown oil;TLC (silica gel; hexane/ethyl acetate=7:3; UV): R_(f) =0.52; ¹ H-NMR(CDCl₃, 200 MHz): 3.90 (s, 2H); 6.65-7.53 (m, 8H) ; MS: 295 (M⁺), 279,239.

d) 6-Bromo-dibenz b,f!oxepine-10-carboxylic acid

Preparation analogous to Example 12 e) from2-(2-chlorophenoxy)phenyl!acetonitrile. Yield: 85%, yellow crystals; ¹H-NMR (CDCl₃, 200 MHz): 6.70-7.50 (m, 7H); 8.32 (dd, 1H).

e) (6-Bromo-dibenz b,f!oxepin-10-yl)methanol

Preparation analogous to Example 12 f) from 6-bromo-dibenzb,f!oxepine-10-carboxylic acid. Yield: 99% crude, brown oil; TLC (silicagel; hexane/ethyl acetate=7.3; UV): R_(f) =0.07; ¹ H-NMR (CDCl₃, 200MHz): 3.54 (s, 2H), 6.70-7.49 (m, 8H).

f) 10-Bromomethyl-6-bromo-dibenz b,f!oxepine

Preparation analogous to Example 12 g) from (6-bromo-dibenzb,f!oxepin-10-yl)-methanol. Yield: 8%, brownish-orange oil; ¹ H-NMR(CDCl₃, 200 MHz): 4.53 (s, 2H); 7.05-7.60 (m, 8H).

EXAMPLE 23 1-(6-Chloro-dibenz bf!oxepin-10-ylmethyl)pyrrolidinehydrochloride

Preparation analogous to Example 2 from 10-bromomethyl-6-bromo-dibenzb,f!oxepine and pyrrolidine. Yield: 20%, beige crystals; melting point:198°-200° C.; ¹ H-NMR (free base) (CDCl₃, 200 MHz): 1.78 (m, 4H) 2.57(m, 4H) 3.62 (s, 2H) 6.89-7.50 (m, 8H) ; MS: 312, 314 (M⁺ +1, freebase).

EXAMPLE 24

In a manner analogous to that described in Examples 1 to 23 it is alsopossible to prepare the following:

N-(1-fluoro-dibenz b,f!oxepin-10ylmethyl)-N-methyl-N-prop-2-ynylamine;

1-(1-fluoro-dibenz b,f!oxepin-10-ylmethyl)pyrrolidine;

N-benzyl-N-(dibenz b,f!oxepin-10-ylmethyl)amine alias10-benzylaminomethyl-dibenz b,f!oxepine;

N-benzyl-N-(dibenz b,f!oxepin-10-ylmethyl)-N-methylamine;

N-(dibenz b,f!oxepin-10-ylmethyl)-N-propyl-N-benzylamine and

N-allyl-N-benzyl-N-(dibenz b,f!oxepin-10-ylmethyl)amine

and salts thereof.

EXAMPLE 25

Tablets each comprising 50 mg of 1-(dibenzb,f!oxepin-10-ylmethyl)pyrrolidine or a salt, for example thehydrochloride, thereof, may be prepared as follows:

    ______________________________________                                        Composition (10000 tablets)                                                   ______________________________________                                        active ingredient       500.0  g                                              lactose                 500.0  g                                              potato starch                                                                 gelatin                 8.0    g                                              talc                    60.0   g                                              magnesium stearate      10.0   g                                              silicon dioxide (highly dispersed)                                                                    20.0   g                                              ethanol                 q.s.                                                  ______________________________________                                    

The active ingredient is mixed with the lactose and 292 g of the potatostarch, and the mixture is moistened with an ethanolic solution of thegelatin and granulated through a sieve. After drying, the remainder ofthe potato starch, the magnesium stereate, the talc and the silicondioxide are mixed in and the mixture is compressed to form tablets eachweighing 145.0 mg and comprising 50.0 mg of active ingredient; ifdesired, the tablets may be provided with dividing notches for fineradaptation of the dose.

EXAMPLE 26

A sterile-filtered aqueous gelatin solution containing 20% cyclodextrinsas solubiliser, comprising as active ingredient 3 mg of 1-(dibenzb,f!oxepin-10-ylmethyl)-pyrrolidine or of a salt, for example thehydrochloride, thereof, is so mixed, with heating, under asepticconditions with a sterile gelatin solution comprising phenol aspreservative that 1.0 ml of solution has the following composition:

    ______________________________________                                        active ingredient         3      mg                                           gelatin                   150.0  mg                                           phenol                    4.7    mg                                           dist. water with 20% cyclodextrins as solubiliser                                                       1.0    ml                                           ______________________________________                                    

EXAMPLE 27

For the preparation of a sterile dry substance for injection, comprising5 mg of 1-(dibenz b,f!oxepin-10-ylmethyl)pyrrolidine or of a salt, forexample the hydrochloride, thereof, 5 mg of one of the compounds offormula I mentioned in the preceding. Examples are dissolved as activeingredient in 1 ml of an aqueous solution containing 20 mg of mannitoland 20% cyclodextrins as solubiliser. The solution is sterile-filteredand, under aseptic conditions, filled into a 2 ml ampoule, deep-frozenand lyophilised. Before use, the lyophilisate is dissolved in 1 ml ofdistilled water or 1 ml of physiological saline. The solution isadministered intramuscularly or intravenously. The formulation can alsobe filled into double-chamber disposable syringes.

EXAMPLE 28

10 000 film-coated tablets, each containing 100 mg of 1-(dibenzb,f!oxepin-10-ylmethyl)pyrrolidine or a salt, for example thehydrochloride, thereof, may be prepared as follows:

    ______________________________________                                        active ingredient       1000   g                                              corn starch             680    g                                              colloidal silicic acid  200    g                                              magnesium stearate      20     g                                              stearic acid            50     g                                              sodium carboxymethyl starch                                                                           250    g                                              water                   q.s.                                                  ______________________________________                                    

A mixture of one of the compounds of formula I mentioned in thepreceding Examples as active ingredient, 50 g of corn starch and thecolloidal silicic acid is processed with a starch paste made from 250 gof corn starch and 2.2 kg of demineralised water to form a moist mass.The mass is forced through a sieve of 3 mm mesh size and dried at 45°for 30 minutes in a fluidised bed drier. The dried granules are pressedthrough a sieve of 1 mm mesh size, mixed with a previously sievedmixture (1 mm sieve) of 330 g of corn starch, the magnesium stearate,the stearic acid and the sodium carboxymethyl starch and compressed toform slightly convex tablets.

EXAMPLE 29

In a manner analogous to that described in Examples 25 to 28, it is alsopossible to prepare pharmaceutical compositions comprising a differentcompound according to any one of Examples 1 to 24 or

1-(dibenz b,f!oxepin-10-ylmethyl)-4-methyl-piperazine;

1-(dibenz b,f!oxepin-10-ylmethyl)-4-(2-hydroxyethyl)-piperazine;

10-allylaminomethyldibenz b,f!oxepine;

10-aminomethyldibenz b,f!oxepine;

10-benzylaminomethyldibenz b,f!oxepine;

10-butylaminomethyldibenz b,f!oxepine;

N,N-diethyl-N-(dibenz b,f!oxepin-10-ylmethyl)amine;

N-(dibenz b,f!oxepin-10-ylmethyl)-N,N-dimethylamine;

N-(dibenz b,f!oxepin-10-ylmethyl)-N-methylamine;

1-(dibenz b,f!oxepin-10-ylmethyl)pyrrolidine;

N- 1-(dibenz b,f!oxepin-10-ylethyl)-N,N-dimethylamine;

N- 1-(dibenz b,f!oxepin-10-ylethyl)-N-methylamine;

1-(8-methoxy-dibenz b,f!oxepin-10-ylmethyl)-4-methyl-piperazine;

(8-methoxy-dibenz b,f!oxepin-10-ylmethyl)-dimethylamine;

(8-methoxy-dibenz b,f!oxepin-10-ylmethyl)-methylamine;

(8-chloro-dibenz b,f!oxepin-10-ylmethyl)-dimethylamine;

(8-chloro-dibenz b,f!oxepin-10-ylmethyl)-diethylamine

or in each case a salt thereof.

What is claimed is:
 1. A 10-aminoaliphatyl-dibenz b,f!oxepine of formulaI ##STR12## wherein alk is a divalent aliphatic radical,R is an aminogroup that is mono or di-substituted by monovalent aliphatic groups atleast one monovalent radical being a substituted or unsubstituted loweralkynyl group, and R₁, R₂, R₃ and R₄ are each, independently of theothers, hydrogen, lower alkyl, lower alkoxy, halogen ortrifluoromethylor a salt thereof.
 2. A compound according to claim 1being N-(Dibenz b,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine or asalt thereof.
 3. A compound according to claim 1 beingN-(dibenzb,f!oxepin-10-ylmethyl)-N-prop-2-ynylamine, N-(1-chloro-dibenzb,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine, N-(7-chloro-dibenzb,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine, N-(8-methoxy-dibenzb,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine,N-(8-tert-butyl-dibenzb,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine, N-(6-chloro-dibenzb,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine, N-(1-fluoro-dibenzb,f!oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine, N-(7-chloro-dibenzb,f!oxepin-10-methyl)-N-methyl-N-prop-2-ynylamine or a salt of any onethereof.
 4. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof together with customarypharmaceutical excipients and carriers.